CA1326107C - Heterocyclic ketones - Google Patents

Abstract

Abstract The invention provides a series of novel heterocyclic ketones of formula I (set out herein-after) and pharmaceutically acceptable base-addition salts thereof, in which the values of R4, L, A, X and Q have the meanings defined in the following specifi-cation. The compounds of formula I are inhibitors of human leukocytic elastase. The invention also pro-vides pharmaceutical compositions containing a com-pound of formula I, or a pharmaceutically acceptable base-addition salt thereof, and processes and inter-mediates for the manufacture of compounds of formula I.

Description

ICI-Am D. 1853-2S
-``` 1326107 . HETEROCYCLIC KETONES
:`
Background and Summary of ehe Invention .
The activity of proteolytic enzymes of the elastase type has been implicated in several patho-logical conditions, for example in arthritis and in pulmonary emphysema. Pharmacological inhibition of an elastase enzyme would be expected to prevent or ameliorate an associated pathological condition.
- Trifl~oromethyl ketone substituted peptide derivatives which are inhibitors of human leukocytic elastase are - described in European Patent Application, Publication num~er 189305 A2.
The present invention relates to certain heterocyclic ketones which are human leukocyte elastase ~HLE) inhibitors making them useful whenever such inhibition is desired, such as for research tools in pharmacological, diagnostic and related studies and in the treatment of tissue degenerative diseases - such as, for example, pulmonary emphysem~ in mam-mals. The invention also includes intermediates useful in the sgnthesis of these heterocyclic ketones, processes for preparing them, pharmaceutical compos~-tions containing such heterocyclic ketones and methods for their use.

Description of the Invention According to the invention there are pro-`- vided compounds of formula I
~" (Formula set out on pages following Examples) .
' ,~

:::
- .

.. . . ..

.

13261~7 wherein the group -Q- is selected from a group con-sisting of (i) ortho-phenylene, optionally bearing one or two substituents independently selected from a group consisting of halogeno, nitro, an amino group of formula -NRgRh, an acylamino group of formula -NHCORm, hydroxy, an acyloxy group of formula -OCORn, (1-4C~alkoxy, (1-4C)alkyl, trifluoromethyl, carboxy, cyano, ~(1-4C)alkoxy~carbonyl, an aminocarbonyl group of formula -CONRPRq (including formula -CONRP2 when RP=Rq), sulfo, sulfonamido of formula S02NRiR~ and (1-3C)hydroxyalkyl; and (ii) a cis-vinylene group of formula -C(Ra~=C(R~- wherein Ra and Rb are each independently selected from a group consisting of hydrogen, nitro, an amino 1~ group of formula -NRgRh, an acyloxy group of formula -OCORn, ~1-4C)alkoxy, (1-6C)alkyl, trifluoromethyl, carboxy, cyano, l(l-4C)alkoxy~carbonyl, an aminocar-bonyl group of formula -CONRPRq (including formula -CONRP2 when RP=Rq)~ a hydroxymethyl group, and phenyl optionally bearing one or two substituents chosen from - a group consiseing of halogeno, nitro, (1-4C)alkoxy, (1-4C)alkyl and trifluoromethyl;
Rg, Rh, Ri, R~, Rm, RP and Rq are each independently selected from a group consisting of hydrogen and (1-4C)alkyl;
Rn is (1-4C)alkyl~
X is selected from a group consisting of oxygen and sulfur;
A is selected from a group consisting of -CO-, -NH.C0- and -O.CO-;
L is selected from a group consisting of ` phenylene, (1-6C)alkanediyl, (2-6C)alkenediyl and phenylene(l-3C)alkyl, optionally containing one double bond in the alkyl portion, with the condition that a ~ .

:

.`` ~, , .

13261~7 carb~n included in a double bond of an alkenediyl or included in an optional double bond of a phenylene-alkyl group is not directly bonded to an oxygen or nitrogen atom of group A; and R4 is selected from a group consisting of acylsulfonamide of formula R5.S(02).NH.Co-, acysul-fonamide of formula R5.Co.NH.S(02)-, sulfonylurea of formula R5.NH.Co.NH.S(02)-, sulfonylurea of formula R5.S(o~).NH.Co.NR6~, and trifluoromethylsulfonamide of formula CF3.S(02).NH- wherein R is selected from a group consisting of (l-lOC)al~yl; trifluoromethyl; t3-lOC)cycloalkyl; (6 or lOC)aryl optionally substituted by 1 to 3 members of a group consisting of halogeno, nitro, amino, 1~ dimethylamino~ hydroxy, methyl, trifluoromethyl, carboxy, phenyl, and 1(1-5C)alkylcarbonyl]amino; and an aromatic heterocyclic group defined as herein below in which up to 3 carbons of the aromatic system may bear a substituent group independently selected from a group consisting of halogeno and trifluoromethyl; and R6 is hydrogen or methyl; and the pharmaceutically accept~ble base-addition salts thereof.
In this specification, the following definitions are used, unless otherwise described:
Halogeno is fluoro, chloro, bromo or iodo.
Aromatic heterocyclic group means a group of from 1 to 15 carbons and from 1 to 4 heteroatoms each of which is independently selected from a group consisting of sulfur, nitrogen and oxygen, and which form 1 to 3 five- or six-membered rings, at least one of which is aromatic. More particularly, such an aromatic heterocyclic group is a monocyclic or fused bicyclic ring system of from 1 to 10 carbon atoms and from 1 to 4 heteroatoms.
- Alkyl, alkanediyl, alkenediyl, etc. denote both straight and branched groups.

. . . ~ .
';` , '~ , _4_ 13261~7 The radicals R4, L and Q may contain chiral centers. The present invention includes compounds of formula I wherein chiral centers included in R4, L
and Q are of the R and/or S configurations. The radical L may contain a double bond; the present invention includes compounds of formula I wherein a double bond included in L is of the E and/or Z~ config-uration.
The compounds of the invention of formula I
can be viewed as tripeptidoyl heterocycles. In general, the preferred compounds of the present invention are of the naturally occurring L-amino acid configuration at the chiral centers identified by *
in formula I~ The methods of synthesis described 1~ below may provide a diastereomeric mixture as a result of the presence of products with both the R and the S
configurations at the chiral center identified by t in formula I. While these diastereomers may be separat-ed, it is not necessary to do so. The preferre~
compounds are those assigned the S configuration at ` the chiral center identified by ~.
As will be appreciated by those skilled in ~`` the art, the activity of the individual isomers is ` not the same, and it is therefore preferred to utilize j~ 25 the more active isomer. The present invention in-cludes both the diastereomeric mixture and the active ~ S and R isomers.
"` A particular value for an optional sub-seituent on Q when Q is o-phenylene, or for an op-tional substituent on Ra or Rb when Ra or Rb is phenyl, or for Rg, Rh, Ri, Ri, Rm, Rn, RP or Rq when the substituent or group is (1-4C)alkyl is, for example, methyl, ethyl, propyl, isopropyl, 2-methylpropyl or t-butyl. A particular value for an optional substituent on Q when Q is o-phenylene, or for Ra or Rb, or for an optional substituent on Ra or Rb when Ra or Rb is phenyl when the substituent or .~

, :
- , . . .. . . .... ~ .-_5_ 132~7 group is (1-4C)alkoxy is, for e~ample, methoxy, ethoxy, propoxy, isopropoxy, 2-methylpropoxy or t-butoxy. A particular value for an optional sub-stituent on Q when Q is o-phenylene or for Ra or Rb when the substituent or group is [(1-4C)alkoxy]-carbonyl is, for example, methoxycarbonyl, ethoxycar-bonyl, isopropoxycarbonyl or t-butyoxycarbonyl. A
particular value for Ra or Rb, when it is (1-6C)alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl, 2-methylpropyl, t-butyl, pentyl, 3-methylbutyl or hexyl~ A particular value for an optional sub-stituent on Q when Q is o-phenylene or for an optional substituene on Ra or Rb when Ra or Rb is phenyl when the substituent is halogeno is, for example, fluoro, chloro or bromo.
A particular value for a ~1-3C)hydroxyalkyl substituent on Q when Q is o-phenylene is, for example, hydroxymethyl, 2-hydroxyethyl or 1,l-dimethylhydroxymethyl~
A particular value of R5 when R5 is tl-lOC)alXyl is, for example, methyl, ethyl, propyl, isopropyl, t-butyl or 4-methylpentyl. A particular value of R5 when R5 is (3-lOC)cycloalkyl is, for example, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, or adamantyl. A particular value for R
~` when R5 is t6 or lOC)aryl is, for example, phenyl or ;~ naphthyl; a particular value for an optional sub-` stituent on aryl when the substituent is halogeno is, `' for example, fluoro, chloro or bromo; and a particular value for an optional substituent on aryl when the substituent is 1(1-5C)alkylcarbonyl]amino is, for example, formylamino, acetylamino, 2-methylpropanoyl-amino or 2,2-dimethylpropanoylamino. A particular value for R when R is an aromatic heterocyclic group is, for example, furyl, thienyl, pyridyl or pyrimi-dinyl; and a particular value for an optional sub-.
, '"' ' ' ''' .':

- - :

-6- ~3261~7 stituent when the substituent is halogeno is, for example, fluoro, chloro or bromo.
A particular value for L when L is phen-ylene is, for example, ~-phenylene or m-phenylene. A
particular value for L when L is (1-6C)alkanediyl is, for example, methylene, ethan-1,2-diyl, ethan-l,1-diyl, propan-1,3-diyl, propan-1,2-diyl, propan-2,2-diyl, butan-1,4-diyl, 2-methylpropan-2,3-diyl, 2-meth-ylpropan-1,2-diyl or pentan-1,5-diyl. A particular value for L when L is ~2-6C)alkenediyl is, for - example, ethen-1,2-diyl, propen-1,2-diyl, propen-1,3-diyl, buten-1,4-diyl, but-2-en-1,4-diyl, penten-1,5-diyl or 3,3-dimethylpropen-1,3-diyl. A particular value for L when L is phenylenetl-3C)alkyl is, for example, ~-phenylenemethyl, 2-(~-phenylene)ethyl or 2-(~-phenylene)-2-propyl; and when the phenylene-(1-3C)alkyl group contains an optional double bond, a particular value for L is, for example 2-(p-phenylene)-ethenyl.
`~ 20 A more particular value for an optional `~ substituent on Q when Q is o-phenylene is, for ex-ample, chloro, dimethylamino, acetylamino, hydroxy, `~ acetoxy, methoxy, methyl, trifluoromethyl, carboxy, `~ cyano, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, amino-` sulfonyl, dimethylaminosulfonyl or hydroxymethyl, ~ including hydroxy, methoxy, carboxy, methoxycarbonyl, `~ aminocarbonyl and hydroxymethyl.
A more particular value for Ra or Rb is, for example, hydrogen, dimethylamino, acetoxy, ~ methoxy, methyl, tri~luoromethyl, cyano, methoxy--~ carbonyl, aminocarbonyl, methylaminocarbonyl, di-~! methylaminocarbonyl, hydroxymethyl, phenyl, chloro-~ phenyl, methoxyphenyl, or trifluoromethylphenyl, -~ 35 including hydrogen.
- A more particular value for R4 is ~ R5.S(O2).NH.CO-, R5.S(O2).NH.CO.NR6_, or CF3S02NH-.
..

.

. .

1326~7 A more particular value for R5 i9, for example, methyl, ethyl, isopropyl, cyclopropyl, cyclopentyl, phenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl, l-naphthyl, 2-thienyl, 2-pyridyl, or chloropyridyl, including methyl, iso-propyl, phenyl and 4-chlorophenyl.
A more particular value for R6 i9 hydrogen.
A more particular value for A is -CO-.
A more particular value for L is, for example, p-phenylene, ethane-1,2-diyl, ethen-1,2-diyl, ~-phenylenemethyl or 2-(~-phenylene)ethenyl, including ~-phenylene.
The particular values listed for radicals, substituents and ranges are for illustration only and do not exclude other defined values or other values within defined ranges for the radicals and substi-tuents.
Within the scope of the invention are .; subgroups, including those in which the heterocyclic 20 ring system containing N, Q and X is:
(a) a benzoxazole wherein X is oxygen and `~ Q is o-phenylene as defined above under (i) in the definition of Q;
(b) an oxazole wherein X is oxygen and Q
~s cis-vinylene as defined above under (ii) in the " definition of Q;
(c) a benzothiazole wherein X is sulfur ~ and Q is o-phenylene as defined above under (i) in the i definition of Q; and td) a thiazole wherein X is sulfur and Q
is cis-vinylene as defined above under (i~) in the definition of Q.
A value of X in formula I of particular interest is oxygen. Values for R4.L.A- in formula I
;- 35 of particular interest include for R4: R5.S(02).-~ NH.CO- and R5.S(o2).NH.Co.NR6-, especially R5.S(02).-_ . .

:

~2~1~7 NH.CO-; for L: ~-phenylene; and for A: -C0-. A
value of R5 of particular interest is 4-chlorophenyl.
Specific compounds of formula I are described in the accompanying Examples. Compounds which are preferred include:
(i) 14-1(4-Chlorophenyl)sulfonylamino-car~onyl~benzoyl]-L-valyl-N-[l-(5-hydroxybenzoxazol-2-yl)carbonyl-2-methylpropyl]-L-prolinamide;
(ii) 14-E(4-Chlorophenyl)sulfonylamino-carbonyl]benzoyl]-L-valyl-N-1l-15-~aminocarbonyl)benz-oxazol-2-yl)carbonyl-2-methylpropyl3-L-prolinamide;
and (iii) [4-1(4-Chlorophenyl)sulfonylamino-carbonyllbenzoyl]-L-valyl-N-1l-lS-(hydroxymethyl)benz-~ 15 oxazol-2-yl~carbonyl-2-methylpropyl]-L-prolinamide.
; The salts of the compounds of formula I
`; include pharmaceutically acceptable base-addition ` salts such as those derived from alkali metal hy-.
` droxides such as sodium hydroxide, alkali metal carbonates and bicarbonates, alkaline earth hydroxides and organic amines~ Such salts may be prepared by dissolving the heterocyclic ketone in a mixture of water and a water-miscible organic solvent, adding an aqueous solution of the base and recovering the salt from the aqueous solution.
The compounds of formula I may be made by processes which include processes known in the chemi-`- cal art for the production of structurally analogous heterocyclic and peptidic compounds. Such processes `` 30 for the manufacture of a compound of formula I as defined above are provided as further features of the invention and are illustrated by the following proced-ures in which the meanings of generic radicals are as defined above (and a radical of formula Q may include a protecting group):
(A) For a compound of formula I, oxidizing a corresponding alcohol of formula III:

, ~326~ ~7 g .
(Formula set out on pages following Examples) III
Methods which are useful include the use of oxalyl-chloride, dimethyl sulfoxide, and a tertiary amine (see Marx, M. et al., J. Org. Chem., 49, 788^793 (1984)); the use of acetic anhydride and dimethyl sulfoxide; the use of dimethyl sulfoxide, 1-(3-di-methylaminopropyl)-3-ethylcarbodiimide hydrochloride and dichloroacetic acid in, for example, toluene (see, e.g. Example 19); the use of chromium trioxide pyri-dine complex in methylene chloride; and the use ofDess-Martin periodinane ll,l,l-triacetoxy-2,1-benzoxi-odol-3(3H)-onel (method of Dess, D. B. et al, J. Or~.
Chem., 48, 4155-56 (1983)). When Q has the value (i) ortho-phenylene and X is oxygen, generally a preferred oxidant is Dess-Martin periodinane; however, when Q
bears an aminocarbonyl group, the use of chromium trioxide pyridine complex or of dimethyl sulfoxide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydro-chloride and dichloroacetic acid is preferred. When an alcohol of formula III contains a basic nitrogen, ~' it is generally preferable to use an alternative method or to protect the basic nitrogen before oxi-dation and deprotect it after oxidation to provide the corresponding compound of formula I.
(B) For a compound of $ormula I wherein R4 has the value R5.S(02).NH.Co-, reacting a corres-ponding compound of formula IV
(FormNla set out in pages following Examples) IV
wherein R7 is carboxy (which compound ~s hereinafter referred to as "acid of formula IV") with a sulfona-mide derivative of formula R5.So2.NH2 in the presence of a dehydrating agent or reacting a reactive deriva-' tive of an acid of formula IV with a sulfonamide, or a salt thereo, of formula R .S02.NH2. Thus, for example, a free acid of formula IV may be reacted with a suitable dehydrating agent, for example, with , , .

~26~07 dicyclohexylcarbodiimide or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, or with a hydrochloride or hydrobromide salt thereof, optionally together with an organic base, for example, 4-dimethylaminopyridine, and with a sulfonamide of formula R5.So2.NH2 in the presence of a suitable solvent or diluent, for example, dichloromethane, at a temperature in the range of, for example, 0 to 50C, but preferably at or near ambient temperature.
Alternatively, a reactive derivative of an acid of formula IV, for example, an acid halide (such as the acid chloride), acid anhydride or a mixed acid anhydride (such as that formed from N,N-diphenylcar-~amic acid and the acid of formula IV by reaction of the sodium salt of the latter acid with N,N-diphenyl-carbamoylpyridinium chloride), may be reacted with an al~ali metal salt (such as the lithiulm, sodium or potassium salt) of the appropriate sulfonamide of fonmula R5.So2.NH2, conveniently at or near ambient temperature and in a suitable solvent or diluent, for example, tetrahydrofuran, N7N-dimethylformamide or dichloromethane.
~x (C) For a compound of formula I wherein R4 has the value R5.Co.NH.S(02)-, reacting a corres-ponding compound of formula IV in which R/ has the value H2N.S(O2)- with an acid of formula R5.CooH
using a similar method eo one of those described above in part (B~.
(D) For a compound of formula I wherein R4 has the value R5.NH.Co.NH.S(02)-, reacting a corresponding compound of formula IV in which R7 has the value H2N.S(O2)- with an isocyanate of formula R .NCO. For exalmple, an intenmediate of formula IV in which R7 is H2N.S(O2)- may be treated with phenyl-isocyanate to provide a corresponding product offonmula I in which R5 is phenyl.

13261~7 (E) For a compound of formula I wherein R4 has the value R5.S(02).NH.CO.NR6-, reacting a corresponding compound of formula IV in which R has the value HNR6- with a sulfonylisocyanate of formula R5.S(02).NCo; or alternatively, for a compound in which R6 has the value H, reacting a corresponding compound of formula IV in which R7 has the value -NCO
with a sulfonamide of formula R5.S(o2).NH2. The reaction may be carried out, for example, at room temperature in a suitable inert organic solvent such as tetrahydrofuran or dichloromethane.
(F~ For a compound of formula I wherein R4 has the value CF3.S(O2).NH-, reacting a corresponding amine of ormula IV in which R7 has the value H2N-with trifluoromethan~esulfonic anhydride, for example,at 0 in an inert solvent such as dichloromethane.
` lG) For a compound of formula I wherein A
has the value -CO-, coupling an acid of formula R4-L-CooH (or a reactive derivative thereof) with an amino ketone of formula V:
(Formula set out on pages following Examples) V
` For example, the coupling may be carried out using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydro-chloride and 4-dimethylaminopyridine or l-hydroxy-benzotriazole in an inert solvent such as tetrahydro-. furan. Similarly, a compound of formula I wherein A
;~ has the value -NH~CO- or -O.CO- may be prepared from '~ a corresponding amino ketone of formula V using a similar method to one described below for the preparation of a starting material alcohol of formula III from an amino alcohol of formula XV.
It may be desired to optionally use a protecting group during all or portions of the above described processes; the protecting group then may be removed when the final compound or a required starting material is to be formed, for example, as described in Examples 5 and 7.

-12- 1326~7 Whereafter, modifying a functional group of a compound of formula I by a conventional method to afford a different compound of formula I, such as, for example, converting an optional carboxy or alk-oxycarbonyl substituent on Q to an aminoacyl sub-stituent, may be carried out.
Whereafter, for any of the above procedures, when a pharmaceutically acceptable salt is required, it may be obtained by reaction of the acidic form of a compound of formula I with a base comprised of a physiologically acceptable cation and a physiologi-cally acceptable anion and affording a physiologically acceptable cation or by any other conventional pro-cedure.
If not commercially available, the necessary starting materials for the above procedures may be made by procedures which are selected from standard techniques of heterocyclic chemistry and peptide chemistry, techniques which are analogous to the `~ 20 synthesis of known, structurally similar compounds, and techniques which are analogous to the above described procedures or the procedures described ~; in the Examples.
As will be clear to one skilled in the art, .' 25 a variety of sequences is available for preparation `~ of the starting materials. According to one of the available routes, a key intermediate of formula XI
may be prepared as shown in Scheme I (set out on pages following Examples) beginning with valinol (formula VII) and utilizing the intermediates of formulae VIII, IX and X as described in Example 1. Alterna-tively, valinol (formula VII) may be coupled w~th an acid of formula IX to afford an alcohol of formula XII; and an alcohol of formula XII may be oxidized to provide an aldehyde of formula XI as a key inter-mediate.

132~7 As shown in Scheme II (set out on pages following Examples) an intermediate aldehyde of formula XI may be converted into a starting material alcohol of formula III, a starting material ketone of formula IV or a starting material amino ketone of formula V.
An aldehyde of formula XI may be reacted with, for example, an alkalai metal cyanide, such as, for example, sodium cyanide or potassium cyanide, to form a cyanohydrin of formula XIII wherein W is CN.
More preferably, an aldehyde of formula XI may be converted into a cyanohydin of formula XIII wherein W
is CN by treatment with acetone cyanohydrin, for `example as described in Example 4a. In addition, ;~15 trimethylsilylcyanide may be used for the transfor-mation, the trimethylsilyl group being removed upon acidic workup~ The hydroxy group of such a ~cyanohydrin may optionally be protected by, for ;example, an acetyl group or a trimethylsilyl or ` 20 t-butyldimethylsilyl group.
;A cyanohydrin of formula XIII wherein W is CN may be converted into a corresponding heterocyclic ~alcohol of formula XIV, either directly or via an `~isolated intermediate using a conventional method.
For example, conversion of a compound o~ formula XIII
wherein W is CN into a corresponding compound of -formula XIV wherein Q has the value o-phenylene as defined above may be carried out using a similar procedure to one described in H~ ,es, E. L. and Wagner, E. C., J. Org. Chem., (1944~, 9, 31. Con-version of a compound of formula XIII wherein W is CN
into a corresponding compound of formula XIV wherein Q
has the value cis-vinylene as defined above may be carried out using a similar procedure to one described in Lora-Tamato, M. et al, Chem. Ber., (1964), 97, 2230, 2234 or in Kitatani, K. et al, Tet. Lett., ~1974), 1531.

.. . . .

~32~7 Alternatively, a cyanohydrin of formula XIII wherein W is CN may be transformed into an imidate of formula XIII where W is -C(NH)OR and R is, for example, methyl or ethyl, preferably as its, for example, hydrochloride salt. An imidate of formula XIII wherein W is -C(NH)OR may be transformed into a corresponding heterocyclic alcohol of formNla XIV;
- the intermediate imidate may be optionally isolated.
The chemistry of imidates has been reviewed in "The ~ 10 Chemistry of Amidines and Imidates," Saul Patai, Ed., ~ohn Wiley and Sons, N.Y., 1975, p. 385 and in Roger, R~ and Nielson, D. G., Chem. Rev., (1961), 61, 1979. Conversion of an imidate of formula XIII
wherein W is -C(NH)OR into a corresponding compound of formula XIV wherein Q has the value o-phenylene as defined above under (i) in the definition of Q may be ` carried out u~ing a similar procedure to one described in Ring, F. E. and Acheson, R. M., J. Chem. Soc., ~1949), 1396; or in Reid, W. et al, Liebigs Ann. Chem., (1964), 676, 114. Conversion of a compound of formula ~ XIII wherein W is -C(NH)OR into a corresponding `~ compound of formula XI~ wherein Q has the value cis-vinylene as defined above under (ii) in the definition of Q and X is oxygen may be carried out using a s~milar procedure to one described in Wiley, R. H., Chem. Rev., (1945), 37, 401; or in Cornforth, J. W., and Cornforth, R. H., J. Chem. Soc., (1947), 96; (1953), 93.
As a further alternative, an imidate of formula XIII wherein W is -C(NH)OR may be hydrolyzed to the corresponding ester of formula XIII wherein W
is -COOR. By using an ester of formula XIII wherein W is -COOR, a corresponding acid of formula XIII
wherein W is -COOH (available by hydrolysis of the ester in a conventional manner), or a different activated derivative of an acid of formula XIII
wherein W is COOH, and a conventional method, a .

~32~7 corresponding compound of formula XIV may be prepared. For example, for a compound of formula XIV
wherein Q is o-phenylene as defined above under (i) in the definition of Q, a similar method to one described in Landenberg, A., Chem. 8er., (1876), 9, 1524; in Galatis, L. C., J. Amer. Chem. Soc., ~1948), 70, 1967;
in "Heterocyclic Compounds'`, Vol. 5, R. C. Elderfield, Ed., J. Wiley ~ Sons, N.Y., 1957, p. 421; in Lankezma, H. P. and Knauf, A. E., J. Amer. Chem. Soc., (1931), 53, 309 and 2654; in Lankezma, H. P. and Vopicka E., ibid., ~1936), 58, 609; or i~ "The Chemistry of Heterocyclic Compounds," P. N. Preston, ~d., (1981), 40, 6-12 may be used. For example, for a compound of formula XIV wherein Q is cis-vinylene as defined above under ~ii) in the definition of Q and X is oxygen, a similar method to one described in Wasserman, H. H.
and Lu, T.-J., Tet. Lett., (1982), 3831; in Dav~dson, ; D. et al, J. Org. Chem., (1937), 2, 328; or in `- Weigand, E. E. and Rathburn, D. W., Synthesis, (1970) .~r 20 648 and J. Chem. Eng. Data, (1973), 18, 237 may be ;~ used. For example, for a compound of formula XIV
wherein Q is cis-vinylene as defined above under ~ii) in the definition of Q and X is sulfur, a similar method to one described in Gabriel, S., Chem. Ber., 25 (1910), 43, 134 and 1283; in Bachstez, M., ibid.
(1947~, 47, 3163; or in Wiley, R. H. et al, Org.
Reactions, (1951), 6, 367 may be used.
Another alternative for the preparation of certain compounds of formula XIV wherein X is sulfur is the use of a thioamide of formula XIII wherein W
is -CSNH2. A thioamide of formula XIII wherein W is -CSNH2 may be obtained, for example, from a corresponding nitrile in a conventional manner, such -- as, for example, treatment with hydrogen sulfide, optionally employing a basic catalyst, such as, for example, triethylamine. Thus, for example, a thio-amide of formula XIII wherein W is -CSNH2 may be -16- i326~ 07 converted into a corresponding compound of formula XIV
wherein Q is cis-vinylene as defined above under (ii) in the definition of Q and X is sulfur by using a similar method to one described in Schmidt, V. et al, Synthesis, (1986), 992 or in Wiley, R. H. et al, Org. Reactions, (1957), 6, 367 and 378.
A different route from an aldehyde of - formula XI to a heterocyclic alcohol of formula XIV
involves the use of a preformed heterocyclic reagent. For example, an organolithium reagent of formula XVI wherein Y is lithium may be reacted ; directly with an aldehyde of formula XI to provide a corresponding alcohol of formula XIV. When X is oxygen, it may be preferred or necessary to use a ` 15 different method. Reagents of formula XVI wherein Y is lithium may be prepared and used as described, for example, in W~sserman, H. H. et al, Tet Lett., ` ~1981), 22, 1737; in Schroeder, R. et al, Liebigs Ann. Chem., (1975), 533; in Beraud, J. and Metzger~
J., Bull. Soc. Chem. France, (1962), 2072; in Shirlet, D. A. and Alley, P. W., J. Amer. Chem. Soc., (1957), 79, 4922; in Ogurat H. and Takahashi, H., J. Org.
Chem., (1974), 39, 1374; in Justin, P. and Hoffmann, H. J., Chem. Ber., (1973), 1 , 594; and in Justi, P. and Sakriss, W., ibid., (1973), 106, 2815.
Alternatively, for example, a 2-trimethyl-silyl heterocyclic reagent of formula XVI wherein Y is trimethylsilyl may be condensed with an aldehyde of formula XI to provide an intermediate 0-trimethylsilyl derivative of a corresponding alcohol of formula XIV.
The alcohol of formula XIV may then be obtained by removal of the trimethylsilyl group using a conven-tional procedure. Reagents of formula XVI wherein Y
- is trimethylsilyl may be prepared and used in a manner similar to those described, for example, for 4-methyl-2-trimethylsilyloxazole, 2-trimethylsilyl-benzothiazole and 2-trimethylsilylthiazole in A.

-17- 1326~7 Dondoni, et al, Tet. Lett., (1985), 26, 5477; in A.
Dondoni et al, J. Chem. Soc., Chem. Commun., (1984), 258; and in A. Medici et al, Tet. Lett., (1983), 24, 2901.
By using a procedure similar to one de-scribed in Levin, J. I. and Weinreb, S. M., J. Org.
Chem., (1984), 49, 4325, an oxazole of formula XIV
wherein X is oxygen and Q is cis-vinylene as defined above under (ii) in the definition of Q may be pre-pared from a corresponding oxazoline (4,5-dihydro-oxazole)~ The oxazoline may be prepared, for example, in a conventional manner from a corresponding inter-; mediate of formula XIII wherein W is CN, -C(NH)OR, -COOR, or -COOH, or by reaction of an appropriate organometallic reagent with a corresponding compound . of formula XI~ (Thiazolines may similarly be prepared -~ and dehydrogenated to afford thiazoles of formula XIV
wherein X is sulfur and Q is cis-vinylene as defined under (ii) in the definition of Q.) An alcohol of formula XIV may be converted into a corresponding amino alcohol of formula XV by removal of the CBZ-group using a conventional method, such as, for example, hydrogenolysis over a palladium on carbon catalyst at about 3 bars pressure and ambient temperature in an appropriate solvent such as, for example, ethanol.
An amino alcohol of formula XV may be converted into a starting material of formula III by reacting the amino alcohol of formula XV with an appropriate acylating agent. For example, when A is -CO-, appropriate acylating agents are activated derivatives of acids of formula R4.L.COOH, for example, activated derivatives thereof generated in situ when using conventional coupling reagents, such as, for example, 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride and l-hydroxybenzotriazole or 4-dimethylaminopyridine, as well as, for example, . ~ . .
.
. . ~

-18- 1326~ 07 acid chlorides of formula R4.L.COCl. When A is -NH.CO-, appropriate acylating agents include iso-cyantes of formula R4.L.NCo. When A is -O-CO-, appropriate acylating agents include chloroformates of formula R4.O.CO.Cl. In general, the acylation is performed in an inert diluent or solvent, such as dichloromethane, tetrahydrofuran or dioxanè, and at a temperature in the range of, for example, 0-60. An organic or inorganic base such as triethylamine, 4-methylmorpholine, ~-dimethylaminopyridine, potassium carbonate or sodium hydroxide may also con~eniently be use~ as an acid acceptor when appropriate.
Starting material keeones of formula IV
~ may also be obtained from an ineermediate alcohol of formula XV as shown in Scheme II. Thus, for example, ior a starting material of formula IV wherein R7 has a value of RZ02C-, H2N.S02-, or R6NH- and RZ has a value defined below, an amino alcohol of formula XV
may be converted into a corresponding alcohol of formula XVII by using a method analogous to one described above for preparation of a compound of formula III and an analogous reagent, such as, for - example ~7.L.COOH, R7.L.COCl, R7.L.NCo or R7.L.O.COCl.
Then, by using a similar oxidation process to one described in process (A), an alcohol of $ormula XVII
may be oxidized to provide a starting material ketone of formula IV. A starting material ketone of formula IV wherein R7 has a value of -NCO may be prepared from a corresponding ketone of formula IV wherein R7 is carboxy by use of a modified Curtius reaction using, for example, diphenylphosphorylazide and triethylamine in benzene or toluene at 80 (See T. Shioiri, K.
Ninomiya and S. Yamada, J. Amer. Chem. Soc., (1972), 94, 6203). A starting material of formula IV wherein ~ has the value carboxy may be prepared by decompos-ing a suitable, corresponding ester of formula IV
wherein R7 has the value RZO2C- in which RZ is a ....
, .
.

-19- ~ 326~

conveniently removed acid protecting group, for example, phenyl, benzyl, or (1-6C)alkyl optionally - bearing an acetoxy, (1-4C)alkoxy or (1-4C)alkylthio - substituent.
A particular value for RZ is, for example, methyl, ethyl, propyl, t-butyl, acetoxymethyl, methoxymethyl, 2-methoxyethyl, methylthiomethyl, phenyl, or benzyl.
It will be appreciated that the decomposi-tion of an ester of fosmula IV wherein R7 is RZO2C-can be performed using any one of a variety of pro-cedures wel~ known in the art of organic chemistry.
~` Thus, it may be carried out, for example, by conven-tional hydrolysis under acid or base conditions, adjusted as necessary to minimize any hydrolytic removal of other functional groups in the molecule.
Alternatively, in certain circumstances, for example, when RZ is t-butyl, it may be preferred to carry out the decomposition using acid catalysis, for example, by treating an ester of formula IV with, for example, trifluoroacetic acid at a temperature of, for example, 0-40C, in a suitable solvent or diluent such as dichloromethane. In addition, when RZ is t-butyl, the decomposition may be performed, for example, by using trimethylsilyl triflate and then water, in a conven-tional manner. Still further, in certain circumstanc-es, for example, when RZ is benzyl, it may be possible eo carry out the decomposition by reductive means, for example, by the use of hydrogen at a pressure of about three bars in the presence of a suitable catalyst, such as palladium or platinum, conveniently on char-coal as a support.
Starting material amino ketones of formula V may be obtained from corresponding alcohols of formula XIV via the corresponding ketones of formula VI. Thus, by using an oxidation procedure similar to one described above in method (A), an alcohol of .

formula XIV may be oxidized tO a corresponding ketone of formula VI, for example, as described in Example 7d and Example 8b. Removal of the N-protect-ing group from a ketone of formula VI will then provide a corresponding starting material amino ketone of formula V. The protecting group conveniently may be removed using, for example, trifluoromethanesulfon-ic acid in dichloromethane at room temperature. It is convenient to isolate an amino ketone of formula V so prepared as its crude trifluoromethanesulfonic acid salt and use it directly for the preparation of a corresponding product of formula I, for example, as described in Example 7f. If an amino ketone of formula V is isolated in the form of its free base, 1~ for example as descri~ed in Example 8c, it is prefer-able to use the material at once because oi the limited stability of the free base.
Starting material ketones of formula IV may also be prepared from corresponding amino ketones of formula V using analogous methods to those described above for the preparation of alcohols of formula XVII
from corresponding alcohols of formula XV.
An alternstive, analogous approach to the starting materials of formulae III, IV and V is out-lined in Scheme III (set out on pages followingExamples). A protected valinal, for example CBZ-valin-al, may be converted into a corresponding protected heterocyclic alcohol of formula XIVa by using a method analogous to one described above for the conversion of a protected aldehyde of formula XI into a protected heterocyclic aloohol of formula XIV. The conversion may be carried out stepwise through analogous inter-mediates of formula XIIIa or directly by using a heterocyclic reagent of formula XVI. An alcohol of formula XIVa may be deprotected to provide an amino ~ alcohol of formula XVa. By coupling with an acid of : formula IX, an amino alcohol of formula XVa may be -;

-21- 13261~7 converted into an alcohol of formula XIV to be used as described in Scheme II. Alternatively, an amine of : formula XVa may be coupled with an acid of formula IXa (prepared by using standard methods or methods analo-gous to those described above) to provide a starting material of formula III, for example, as described in Example 19. In addition, an amine of formula XVa may be coupled with an acid of formula IXb (prepared by using standard methods or methods analogous to those - 10 described above) to provide a compound of formula XVII, which may be converted into a startin~ material of formula IV.
A further approach to starting materials of formulae IV and V, as well as to compounds of formula I, also involves the use of organometallic reagents of formula XVI wherein Y is lithium, especially when X
is sulfur, as illustrated in Scheme IV and Example 13 and Example 14. Thus, for example, a suitably amino-protected, N,N-disubstituted valinamide, such as benzyloxycarbonyl protected, N-methoxy-N-methylvalin-amide of formula XX, may be treated with a lithiated heterocycle, such as 2-lithiothiazole or 2-lithio-benzothiazole, to afford a corresponding ketone of formula XXI~ Removal of the amino-pro~ecting group from a compound of formula XXI by a conventional method affords a corresponding aminoketone of formula XXII. By coupling an acid of`formula IX with an amine of formula XXII, a corresponding ketone of formula VI
may be obtained. As described above, a ketone of formula VI may be converted into a starting material of formula V, which starting material of formula V may be further converted into a starting material of formula IV. By coupling an acid of formula IXa with an amine of formula XXII, a corresponding product of formula I may be obtained. Similarly, by coupling an acid of formula IXb with an amine of formula XII a corresponding starting material of formula IV may be -22- 13261~7 obtained directly. Also, by use of analogous method-ology to that described for the conversion of an amide of formula XX into an amino ketone of formula XXII, other intermediate compounds, such as those of for-mula XXIII, formula V and formula IV wherein R is HNR6-, may be obtained.
As will be clear to one skilled in the art, the order of steps in the sequences leading to the starting materials and products of the invention may be altered if appropriate considerations relative to coup~in~ methods, racemization, deprotection methods, etc. are followed.
Inhibition Measurements:
.
The potency of compounds of the invention to act as elastase in~ibitors is initially determined by the ability of a compound of the invention to inhibit the action of human leukocyte elastase (HLE) on a low molecular weight peptide substrate. The potency of an inhibitor is evaluated by obtaining a kinetic determina-tion of ehe dissociation constant, Ki, of the complex formed from the interaction of the inhibitor with HLE.
The substrate used was the anilide meehoxysuccinyl-alanyl-alanyl-prolyl-valine-p-nitroanilide as described by Nakajima, K~ et al. in J. Biol. Chem., 245, 4027-4032 (1979) and by Teshima, T. et al. in J. Biol.
Chem~, 257, No. 9, 5085-5091 ~1982)~ The HLE enzyme used in these studies may be obtained from Elastin Products of St. Louis, Missouri or can be purified according to Viscarello, B. R. et al. in Preparative Biochemistry, Vol. 13, pages 57-67, (1983) as also described in European Patent Application, Publication number 189305 A2. From the thus purified HLE, a standard rate of production of p-nitroaniline was measured at 25C spectrophotometrically in the visible spectrum at 410 nanometers with automatic data acqui-sition from a a Cary 210 spectrophotometer obtained from Varian Associates. Reactions were initiated by -23- 1326~7 injection of 10 microliters of the HLE solution into a 3 milliliter cuvette containing 2.89 milliliters of buffer (10 millimolar sodium phosphate, 500 millimolar NaCl, pH 7.6). 50 microliters substrate solution in DMSO, and 50 microliters of DMSO. Initial, steady-state reaction velocities of p-nitroaniline production were calculated by a fit of the experimental data to a linear dependence on time by linear least squares.
This velocity, determined with no inhibitor present, was used as a standard in the calculation of inhibitor Ki values~
In general, the heterocyclic ketones of the present invention are not "slow-binding" inhibitors of HLE; however, if the heterocyclic ketones are found to be "slow-binding'` inhibitors of HLE, special methods of analysis to accurately determine Ki values for their inhibition of HLE are carried out. (See Williams, J. W. and Morrison, ~. F., Meth. Enz~ 63, 437 (1979) for a description of these methods.) In a typical experiment, 2.89 ml of buffer (10 millimolar sodium phosphate, 500 millimolar sodium chloride, pH
7.6), 50 microliters of inhibitor solution in DMS0, and 50 microliters of substrate solution in DMSO are added to a 3 milliliter cuvette. The cuvette is stoppered, inverted several times to mix its contents and maintained at (25C) in the spectrophotometer.
After a period of five minutes to allow the reaction solution to come to thermal equilibrium, 10 micro-liters of stock enzyme solution are added to the cuvette to initiate the reaction. Duplicate or ; triplicate runs are done at zero inhibitor concen-tration and at least three non-zero inhibitor con-centrations. Ki values are calculated according to methods outlined in the above reference by Williams and Morrison. The Ki values for selected compounds are less than 10 M. For example, the K. value for the compound of Example 1 is 3.3 x 10 lOM.

. .
:

-24- 1 326~7 Animal Models Animal models of emphysema include intratra-cheal (i.t.) administration of an elastolytic protease to cause a slowly progressive, destructive lesion of 5 the lung. These lesions are normally evaluated a few weeks to a few months after the initial insult.
However, these proteases also induce a lesion that is evident in the first few hours. The early lesion is first hemorrhagic, progresses to an inflammatory 10 lesion by the end of the first 24 hours and resolves in the first week post insult~ To take ad~antage of this early lesion, the following model was used.
Hamsters are first lightly anesthetized with Brevital. Phosphate buffered saline (PBS) pH 7.4, 15 either alone or con~aining 400 ~g of human leukocyte elastase (HLE~, is then administered directly into the trachea~ Twenty-four hours later the animals are killed and the lungs removed and carefully trimmed of extraneous tissue~ Following determination of wet 20 lung weight, the lungs are lavaged with PBS and total lavagable red and white cells recovered are deter-mined. The values for wet lung weights, total lavagable red cells and total lavagable white cells are elevated in a dose-dependent manner following ` 25 administration of HLE. Compounds that are effective elastase inhibitors can prevent or diminish the severity of the enzyme-induced lesion resulting in lower wet lung weight and reduced values for total lavagable cells, both red and white, re~ative to `` 30 administration of HLE alone. Compounds can be evaluated by administering them either with or at ? various times prior to administration of HLE to ` - determine their utility in preventing an HLE lesion.
Compounds of this invention produced statistically 35 significant reductions in wet lung weight and total ;~ lavagable cells relative to HLE alone.

..

-25- 132~7 Compounds of the present invention which were tested exhib}ted activity in at least one of the tests described above under Inhibition Measurement or Animal Model. It should be noted that there was not always a direct correlation between the activities of the compounds measured as Ki values in the Inhibition Measurement test and the reduced values for total lavagable cells and wet lung weights relative to the administration of HLE alone obtained in the Animal Model test~ In general, no overt signs of scute toxicity were noticed for compounds of the present invention tested in the Animal Model.
The compounds of the present invention may be administered to a warm-blooded animal in need thereof for treatment of a tissue degenerative disease, particularly a human, in particular for the treatment of emphysema. The preferred mode of ad-ministration may be via a powdered or liquid aerosol.
In a powdered aerosol, compounds of the invention may be administered in the same manner as cromolyn sodium via a 'Spinhaler' (a trademark) turbo-inhaler device ~' obtained from Fisons Corp. of Bedford, Massachusets at a rate of about 0.1 to 50 mg per capsule, 1 to 8 capsules being administered daily for an average human. ~ach capsule to be used in the turbo-inhaler contains the required amount of a compound of the invention with the remainder of the 20 mg capsule being a pharmaceutically acceptable carrier such as ; lactose. In a liquid aerosol, the compounds of the invention are administered at the rate of about 100 to 1000 micrograms per "puff" or activated release of a standard volume of propellant. The liquid aerosol would be given at the rate of 1 to 8 puffs per day with variation in dosages due to the severity of the conditions being treated, the weight of the patient and the particular size distribution of the aerosol since smaller particles will achieve greater lung ~, ;

''';~: '`....... ''.' ' ~

penetratio~. Propellants, e.g., a fluorinated hy-drocarbon or isobutane, containers, valves and actuators for liquid aerosols are described by L.
Lachman et al. in "The Theory and Practice of Industrial Pharmacy," Lea and Febiger, Philadelphia (1976).
Alternatively, the mode of adminstration may be oral or parenteral, including subcutaneous deposit by means oi an osmotic pump. The compounds of the invention may be conventionally formulated in an oral or parenteral dosage form by compounding about 10 to 250 mg per unit of dosage with conventional vehicle, excipient, binder, preservative, stabilizer, flavor or - the like as called for by accepted pharmaceutical practice, e~g. as described in U.S. Patent No.
3,755,340. For parenteral administration, a 1 to 10 ml intravenous, intramuscular or subcutaneous in-jection would be given containing about 0.02 mg to 10 mg/kg of body weight of a compound of the invention 3 or 4 times daily. The injection would contain a compound of the invention in an aqueous isotonic sterile solution or suspension optionally with a preservative such as phenol or a solubilizing agent ` such as ethylenedia~inetetraacetic acid ~EDTA).
The invention will now be illustrated by the following non-limiting examples in which, unless stated otherwise:
(i) temperatures are given in degrees c Celsius ~C); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25;
~ ii) evaporation of solvent was carried out using a rotary e.vaporator under reduced pressure (600-4000 pascals; ~.5-30 mm Hg) with a bath temperature of ` 35 up to 60;
`, ~iii) flash chromatography was carried out on Merck ~ieselgel (Art 9385) lobtained from E. Merck, : , : .

-27- 132~7 Darmstadt, W. Germany~; if "acidic silica gel" is indicated, material custom prepared by J. T, Baker Chemical Co., Phillipsburg, NJ, USA, and having a pH
of about 6 when slurried in water was used; thin layer chromatography (TLC) was carried out on Analtech 0.25 mm silica gel GHLF plates (Art 21521), obtainable from Analtech, Newark, DE, USA;
(iv) in general, the course of reactions was followed by T~C and reaction times are given for illustration only;
(v) melting points are uncorrected and (d) indicates decomposition; the melting points given are those obtained for the materials prepared as de-scribed; polymorphism may result in isolation of ma-terials with different melting points in some pre-parations;
(vi) all final products were essentially pure by TLC and had satisfactory nuclear magnetic resonance (NMR) spectra and microanalytical data;

2~ ~vii) yields are given for illustration only and are not necessarily those which may be obtained by diligent process development; preparations were repeated if more material was required (viii) when given, NNR data is in the form of delta values ~or major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane tTMS) as an internal standard, determined at 80 MHz or 250 NHz using CDC13, DNS0-d6 or CD30D as solvent; con-ventional abbreviations for signal shape are used, for example: s, singlet; d, doublet; m, multiplet; br, broad; etc.; in addition "Ar" signifies an aromatic group or signal;
(ix) reduced pressures are given as absolute pressures in pascals (Pa); other pressures are given as gauge pressures in bars;
(x) chemical symbols have their usual meanings; the following abbreviations have also been ~ .
:- :
:`' . ' -28- 13261~7 used: min (minutes), hr (hours), v (volume~, w (weight); mp (melting point), 1 [liter(s)], ml (milliliters), g tgram(s)l, mg lmilligram(s)];
(xi) solvent ratios are given in volume:
volume (v/v) terms; ratios of solids are given in weight:weight (w/w) terms;
(xii) mass spectra (MS) were run with an electron energy of 70 electron volts in the chemical ionizaton mode using a direct exposure probe; when given, only peaks ten percent of the base peak and larger are reported; and (xiii) when high pressure liquid chromato-graphy (HPLC) data is reported, tR (retenti~n time~ is given min, FR (flow raee) is given in ml/min, Col A is a 'Zorbax' (a trademark) ODS an~lytical column (4.6 mm x 25 cm) and Col B is a `Phenomenex' (a trademark) 'Zorbax' C-8 analytical column (4.6 mm x 35 cm).
- NOMENCLATURE: For uniformity and clarity, "amino acid sequence" type names are used whenever possible.
In general, a stereochemical identification of a `~ chiral center as (S) indicates that the product is estimated to contain at least 95% of the (S)-isomer at i the center indicated; the absence of an identification `~ of stereochemistry at a chiral center indicates a mixture of isomers which is not necessarily 1:1 at the center indicated.

.

. .

~; , .

-29_ ~32~7 Example 1 (S)-[4-[(4-Chlorophenyl)sulfonylaminocarbonyl]benzo-yl]-L-valyl-N-[1-(2-benzoxazolyl)carbonyl-2-methyl-propyl]-L-prolinamide (Formula I, heterocycle con-taining X, N and Q=2-benzoxazolyl, A=CO, L=p-phenylene, R4=R5.S~O2).NH.CO-, R5=4-ClC6H4).

a. N-Benzyloxycarbonyl-L-valinol.

Benzyl chloroformate (91.0 g, 95X purity) was added dropwise over a period of 1 hr to a pre-cooled (0) solution of L-valinol (50.0 g) and tri-ethylamine (60.0 g) in chloroform (1500 ml). The reaction mixture was stirred for 1 hr at 0 and then allowed to warm to room temperature over 2 hr. After the reaction mixture was evaporated, ethyl acetate (1500 ml) was added to the residue; and the organic solution was washed with lN NaOH and brine, dried (MgSO4), and evaporated. The resulting residue was purifed by flash chromatography, using a stepwise gradient of ether:hexane (1:5) followed by ether, to give the product (91.4 g) as a white waxy solid; TLC, Rf-0.23, hexane:ether (50:50).

b. N-Benzyloxycarbonyl-L-valinal.

A solution of dimethylsulfoxide (107.2 g) in ` 30 methylene chloride (150 ml) was added dropwise over 0.5 hr to a precooled (-60), stirred solution of oxalyl chloride (87.1 g) in methylene chloride (800 ml) under a nitrogen atmosphere. The temperature of the mixture rose to -45. The reaction mixture was then warmed to -30. A solution of the product of Example la (81.5 g) in methylene chloride (300 ml) was added dropwise over 45 min at -30~. The reaction -30- 1326~7 mixture was stirred f~r 50 min at -25, cooled to -40 and a solution of diisopropylethylamine (177.4 g) in methylene chloride (250 ~13 was added dropwise over 45 min at -40. The ~eaction ~ xture was stirred for 1 hr as it warmed to ro~m *~m~ratur;e. The reaction -- mixture was diluted with ~*hylene chloride (1500 ml), and the organic phase ~a~ was~ed ~it~ lN ~Cl and evaporated to give ~t~e-p~od~ct ~9~ g) as a green oil which was used immediately without further purifi-cation; TLC, Rf=0.48, h~xane:e~her (50:50).

c. N-Benzyloxycar~n~ ~lisal ~iethylacetal.

Triethyl or~hD~m ~E~e (~DB g), absolute ethanol (800 ml) and ~t~lueDesulf~ic acid mono-`~ hydrate ~5.0 g) were added to a por~ion of the product of Example lb (81 g). ~e ~i~tur~ was stirred for lO
min at room temperature and ~en evaporated. The resulting residue was dissol~ed in Dther, washed with saturated aqueous NaHC03, ~ri~d ~a2S04), and evapo-rated to give a crude product ~h~eh was purified by flash chromatography ~sing ~ step~d~e gradient of hexane through mixtures of ~u~hy~ene chloride:hexane to ethyl acetate:methylene ~hlos~de (30:70) to give the product (84.7%) as a pale yellow oil; TLC, Rf=0.21, methylene chloride:petroleum ether t50:50).

d. L-Valinal diethylacetal ~FoTmula VIII).

A mixture of ti~e ~rDdu~ ~repared using the method of Example lc (14~.8 g) and lOX palladium on carbon (lO g) in ethyl acet~$~ (1500 ml) was stirred under H2 (l bar~ until 2500 ml o~ ~ were consumed.
Twice during this time the ~eaction was interrupted and lOX palladium on carbo~ (10 g) was added. The reaction mixture was then iiltered through a pad of diatomaceous earth. lOZ Palladium on carbon (10 g) was added and the reacion mixture was again stirred under H2 until 10.92 liters of H2 were consumed. The reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated under vacuum to gi~e the product t78.8 g) as a pale yellow oil;
D25=+7.8.

e. Benzyloxycarbonyl-L-valyl-L-proline methyl ester.
To a cooled (0-S) solution of ~-benzyloxy-carbonyl-L-valine (4~0.0 g) in dry N,N-dimethyl-formamide ~3.0 liter) was added l-hydroxybenzotriazole hydrate (483.3 g); and the reaction mixture was stirred for ~0 min, followed by the addition of a slurry of L-proline methyl ester hydrochloride (296.4 g) and triethylamine (186.6 g) in N,N-dimethyl-formamide (1.5 liter). After the resulting mixture was cooled to 0~ (3-dimeehylaminopropyl)-3-ethyl-carbodiimide hydrochloride (377.6 g, 1.97 mol) in N,N-dimethylformamide ~500 ml) was added. The reaction mixture was stirred at 0-5 for 3 hr and then allowed to warm gradually to room temperature.
Stirring was continued for 65 hr, and the mixture was filtered and evaporated. The residue was partitioned between ether and lN HCl, and the precipitate which formed was removed by filtration. The etheral layer was then separated; washed with water, saturated aqueous NaHCO3 and brine; dried (MgSO4~; and evapo-rated. The crude ester was purified by flash chroma-tography using a gradient elution of methylene chloride, then ~ethanol:methylene chloride (1:99), (2.5:79.5), and, finally, (5:95). The impure material from the first column was rechromatographed using a gradient elution of methylene chloride:hexanes ~1:3), methylene chloride, and, finally, methanol:methylene ... , . .:

.
;; - ~ . , :- .
. ':' ' , '' '' :

chloride (2:98). The combined chromatographies afforded the ester (596.9 g, 92%) as a colorless oil; TLC, Rf=0.45-0.60, methanol:methylene chloride (5:95); MS, m/e=363(M+l, base), 319, 255, 130, 91.
Analysis for ClgH26N2O5.0 25 H2O
Calculated: C, 62.19; H, 7.28; N, 7.68 Found: C, 62.19; H, 7.12; N, 7.51 f. Benzyloxycarbonyl-L-valyl-L-proline (Formula IX).
To a solution of the product of Example le (595.0 g) in methanol t4.8 liter) was added lN NaOH
(1.80 liter), and the solution was stirred for 18 hr.
The methanol was evaporated, and the aqueous layer was acidified (pH 2) with lN HCl and extracted with methylene chloride. The organic extracts were washed with brine, dried (Na2SO4) and evaporated to afford the acid (520.2 g, 90~) as an analytically pure, white solid; MS, m/e=349(M+l, base), 305, 241, 206, 116, 91.
Analysis for C18H24N25 3 H2O
Calculated: C, 61.11; H, 7.01; N, 7.92 Found: C, 61.12; H, 6.86; N, 7.68 ~`
g. (S)-Benzyloxycarbonyl-L-valyl-N-~l-(diethoxy-methyl)-2-methylpropyl]-L-prolinamide (Formula X).

Isobutyl chloroformate (57.8 g) was added in one portion to a solution of the product of Example lf (154.3 g) and 4-methylmorpholine (42.8 g) in dry tetrahydrofuran(280 ml) at -20. After stirring for 10 min, the mixture was cooled to -40 and aminoacetal prepared as described in Example 1, parts a-d (74.2 g) in tetrahydrofuran(700 ml) was added. The mixture was allowed to warm to room temperature and stir for 16 hr before it was filtered and evaporated. The 132~
residue was dissolved in ethyl acetate; washed with lN
HCl, saturated aqueous NaHCO3 and brine; dried (Na2SO4~; and evaporated. The crude product was purified by flash chromatography eluting with a gradient of methylene chloride, then ethyl acetate:
methylene chloride (4:96), (8:92~, ~25:75), (50:50), and, finally, ethyl acetate to afford 156 g of pro-duct. The impure fractions were rechromatographed on a high pressure liquid chromatograph (Waters Prep 500 HPLC using 2 silica gel cartridges), eluting with ethyl acetate:methylene chlor~de, to afford an ad-ditional 22 g of product; TLC, Rf=0.47, ethyl ace-tate:methylene chloride (25:75).

h. (S)-Benzyloxycarbonyl-L-valyl-N-(l-formyl-2-methylpropyl)-L-prolinamide (Formula XI).

A solution of the product of Example lg (16~97 g) in acetone (800 ml) was added to a solution of concentrated HCl (45 ml) in water (2.6 liter), and the solution was stirred at room temperature for 16 hr. Ethyl acetate was added and the aqueous layer was extracted with ethyl acetate. The organic extracts were dried (MgSO4) and evaporated to afford 12,8 g of yellowish oil; TLC, Rf=0.61, ethyl acetate:hexanes (4:1); MS, m/e=432(M+l, base), 199.

-` h-l. A preferred method for conversion of the acetal product of Example lg into the aldehyde product of Example lh is as follows:

To a stirred solution of the acetal product of Example lg (18.80 g) in acetone (800 ml) under nitrogen was added p-toluenesulfonic acid ~360 mg).
The mixture was stirred 23 hr and the solvent evaporated. The residue was diluted with ethyl :. . : '., ' `
, ~34~ i ~ 2 6 1 ~7 acetate and washed (saturated sodium bicarbonate, brine), dried (Na2SO4) and evaporated to afford 15.68 g (97~) of the aldehyde product of Example lh; TLC, Rf=0.48, acetone:hexanes (45:55); MS, m/e=460(M+2~), 433 (M~2), 432(m+1), 331, 199.

i. Benzyloxycarbonyl-L-valyl-N-[l-(cyanohydroxy-methyl)-2-methylpropyl3-L-prolinamide (Formula XIII, W=CN).
Solid KCN (7.74 g, 119 mmol) was added to a solution of the product of Example lh, (12.8 g~ in tetrahydrofuran(l50 ml) and water (128 ml). The ~` resulting mixture was stirred for 4.5 hr, and then partitioned between ethyl acetate and water~ The aqueous layer was extracted with ethyl acetate; the combined organic layers were washed with saturated aqueous NaHCO3 and brine, dried (lOX (w/w) K2CO3/
- Na2SO4) and evaporated to afford 14.0 g of crude cyanohydrin; TLC, Rf=0.17, acetone:hexanes (1:3).

i-l. An alternative, preferred procedure for preparation of the product of Example li is described in Example 4a.
. Benzyloxycarbonyl-L-valyl-N-~1-(2-benzoxazolyl)-hydroxymethyl-2-methylpropyl]-L-prolinamide (Formula XIV, heterocycle containing X, N and Q=2-benzoxazolyl).
A solution of acetyl chloride (9.50 ml) in ether (15 ml) was added to a solution of absolute ~` ethanol (10.8 ml) in ether (33 ml) at 0 over a period of 20 min. After stirring at 0 for an additional 15 min, the product of Example li (used without further purification) (7.70 g) in chloroform (15 ml) was added, and the solution was stirred at 0 for 16 hr.

-35- ~326~7 The solvents were evaporated, the residue was dis-solved in absolute ethanol (80 ml), and 2-aminophenol (1.83 g) was added. After heating at 60 for 3 hr, the mixture was dissolved in ethyl acetate, washed with lN NaOH and brine, dried (lOX ~w/w) K2C03/
Na2S04), and evaporated. The crude product was flash chromatographed, eluting with acetone:hexanes (3:17), to afford 3 fractions of yellowish foam: fraction one~ TLC, Rf=0.30, acetone:hexane (3:17), MS, m/e=~51(M+l), one isomer, 136 mg; fraction two, TLC, Rf=0.25-0.17, acetone:hexane (3:17), all four isomers, 1.77 g; fraction 3, TLC, ~f=0.17-0.08, acetone:hexane (3:17), three isomers, 2.45 g.

k. L-Valyl-N-[1-(2-benzoxa201yl)hydroxymethyl-2-methylpropyl~-L-prolinamide (Formula XV, hetero-cycle containing X, N and Q=2-benzoxazolyl).

; A mixeure of 10% palladium on carbon (300 mg, 50~ water wet) and the product of Example 1;, fraction three (2.45 g) in ethanol (100 ml) was hydrogenated in a shaker at 3~4 bar for 6 hr after which time an additional amount of palladium on carbon (300 mg) was adde~ and the mixture hydrogenated for an additional 3 hr~ The mixture was filtered through diaeomaceous earth and the solvent evaporated. The residue was dissolved in ethyl acetate, extracted into lN HCl and the aqueous acid layer was washed with ethyl acetate, basified with lN NaOH and, extracted with ethyl acetate~ The organic solvent was evapo-; rated to afford 1.40 g (76X) of solid. Rf=0.0-0.15, methanol:chloroform (1:19); MS, m/e-471 (M+l), 399.

. ~ . , -36- 132~1~7 1 l4-~(4-Chlorophenyl)sulfonylaminocarbonyl]-benzoyl~-L-valyl-N-[1-(2-benzoxazolyl)hydroxy-- methyl-2-methylpropyl]-L-prolinamide (Formula III, heterocycle containing X, N and Q=2-ben-zoxazolyl, A=CO, L=~-phenylene~ R4=R5.S(o2).NH.-CO-, R =4-ClC6H4).

1-~3-Dimethylaminopropyl)-3-ethylcarbodi-imide (710 mg) was added to a solution of the product of Example lk (1.38g), l-hydroxybenzotriazole (983 mg) and 4-lt4-chlorophenyl)sulfonylaminocarbonyllbenzoic - acid (see parts n and o below) tl.l2 g) in tetrahydro-furan (18 ml); and the solution was stirred at room temperature $or 16 hr. The mixture was partitioned between water and ethyl acetate; the organic phase was washed with lN HCl and brine, dried (MgS04), and evaporated. The crude product was purified by flash chromatography, eluting with ethyl acetate:ether:-acetic acid (60:40:2 drop/ml~, to afford 1.2 g of solid; TLC, Rf-0.42, methanol:chloroform:acetic acid `~ (5:95:1 drop/ml); MS, mle=738tM~ 421, 318.
Analysis for C36H40ClN5O8S 1.4 H20:
` Calculated: C, 56.64; H, 5.65~ N, 9.17 Found: C, 56.97; H, 5.39; N, 8.67 m. (S)-t4-~4-Chlorophenyl)sulfonylaminocarbonyl~-benzoyl]-L-valyl-N-11-(2-benzoxazolyl)carbonyl-2-methylpropyl]-L-prolinamide (Formula I, hetero-~- cgcle containing X, N and Q=2-benzoxazolyl, A=CO, L-p-phenylene, R4-R5.S(o2).NH.Co-, R5-4-ClC6H4).

Trifluoroacetic acid (0.712 ml) was added to a solution of the product of Example 1, Part 1 (1.15 g) and Dess-Martin periodinane (2.65 g) in methylene chloride ~15 ml); and the solution was stirred at room temperature for 16 hr. The resulting suspension was partitioned between ethyl acetate and lN HCl. The ^ ` ~ ' .
.,. `'; ` , ` ' . - ~ ..

-37- ~3261~7 organic solution was washed with two portions of 1:1 (w/w) saturated aqueous Na2S2O3: NaHCO3, saturated aqueous NaHCO3 and brine; dried (MgSO4) and evapo-rated The crude product was purified by flash chromatography eluting with tetrahydrofuran:methylene chloride:acetic acid (2~5:97.5:1 drop/ml) to afford 889 mg of solid. A second purification was perfonmed using flash chromatography on acidic silica gel, eluting with methanol:chloroform (2.5:97.5~, to afford the title compound (701 mg~ as a solid; TLC, Rf=0.4~, ethyl acetate:hexanes:acetic acid (65:35:1 drop/ml); HPLC, tR--9.27, Col B, FR-4, water:acetoni-trile:tetrahydrofuran:trifluoroacetic acid t55:35:
15:0.1); MS, m/e=736(M~1), 718, 421, 298.
Analysis for C36H38ClN5O8S-1-25 H2O
Calculated: C, 56.12; H, 5.47; N, 9.09 Found: C, 56.24; H, 5.07; N, 8.74 The benzoic acid intermediate used for coupling in part 1. may be prepared as follows:

n. l,l-Dimethylethyl 4-~(4-chlorophenyl)sulfonyl-aminocarbonyllbenzoate.

A 5-liter 3-neck round bottom flask was equipped with a mechanical stirrer and nitrogen inlet.
; Nethylene chloride (2 liters) was placed in the reaction flask and terephthalic acid mono-t-butyl ester (127.5 g), 4-dimethylaminopyridine (70.06 g), and 4-chlorobenzenesulfonamide (110.04 g) were added ` sequentially using methylene chloride (400 ml) to ` wash down the solids. 1-(3-Dime~hylaminopropyl)-` 3-ethylcarbodiimide hydrochloride was added in portions over 10 min using methylene chloride (100 ml) to wash down the solid. After the reaction mixture was stirred overnight at room temperature, it . .

.
~ .
: , ~

. . .. .
- 1. . .. . . . .
.

-38- 13261~7 was evaporated to dryness. The residue was par-titioned between ethyl acetate and water. The organic solution was washed with 20Z (w/v) aqueous citric acid, saturated aqueous NaHCO3 and brine; dried (Na2SO4);
and evaporated to a white solid. After drying in a vacuum oven at 50, the ester (277g, lOOX) was obtained in a sufficiently pure sta~e to be used directly for the next step; TLC, Rf~0.43, methanol:chloroform (15:85). (Further purification was possible by recrystallization from ethanol/water;
mp above 300).

.
. 4-1(4-Chlorophenyl)sulfonylaminocarbonyl]benzoic acid~
A 3-liter 3-neck round bottom flask was equipped with a mechanical stirrer and a CaC12 drying tube. Trifluoroacetic acid (1300 g) was added and .~ cooled to 0, and the product of Example ln (79.5 g) was added. Initially, the solid dissolved, giving a clear solution. After 10-15 min, a heavy precipi~ate of product formed; and it was difficult to stir the reaction mixture. Vigorous stirring with the mechanical stirrer was essential to drive the reaction to completion. The reaction mixture was ` stirred at 0-5 for 1 hr before it was poured into 1500 ml of icelwater and stirred for 2 hr. The resulting solid was filtered and dried. The white solid (61.5 g, 91%) obtained was recrystallized from 1600 ml absolute ethanol/1600 ml water to yield the benzoic acid (54 g, 80%) as white needles; mp 286-288; TLC, Rf=0.7, methanol:chloroform:acetic acid (10:90:1) .

. .

.

~39~ 132~107 Example 2 [4-(Methylsulfonylaminocarbonyl~benzoyl]-L-valyl-N-[1-(2-benzoxazolyl)carbonyl-2-methylpropyl]-L-prolin-amide ~Formula I, heterocycle containing X, N andQ=2-benzoxazolyl, A=CO, L=p-phenylene, R4=R5.S(o2).-NH.CO-, R5=CH3~.

a. ~lS)-l4-(1,1-Dimethylethoxy~carbonylbenzoyl~-L-valyl-N~ 2-benzoxa~olyl)hydroxymethyl-2-methylpropyl]-L-prolinamide (Formula XV~I, heterocycle containing X, N and Q=2-benzoxazolyl, R7.L.A=4-l~CH3)3COCO]C6H4C0).
1-(3-Dimethylaminopropyl)-3-ethylcarbodi-imide hydrochloride (510 mg) was added to a solution of product prepared by the method of Example lk lmaterial prepared according to the method of Example lj and obeained in the (lS)-form was treated according to the procedure of Example lk and obtained in the (lS)-form] (1.00 g), l-hydroxybenzotriazole (720 mg), and terepthalic acid mono-t-butyl ester (560 mg) in tetrahydrofuran(5 ml) at 0; and the solution was allowed to warm to room temperature and stirred for 16 hr. The mixture was partitioned between water and ethyl acetate, the organic phase was washed with ~` lN HCl (twice), saturated sodium bicarbonate (twice) and brine, dried (MgSO4) and evaporated. The crude product was purified by flash chromatography, eluting w*th acetone:hexane (4:6), to afford the product (1.08 g, 73~) as a solid; TLC, RfS0.7, acetone:hexane (45:55); MS, m/e3621 (M+l), 649, 622, 565, 318.
Analysis for C34H44N407Ø4 H2O:
Calculated: C, 65.03; H, 7.19; N, 8.92 Found: C, 65.06; H, 7.05; N, 8.72 `:

...
- , . . .
- , ., ., ~

` ~ ' _40_ 1326107 b. (S)-[4-(1,1-Dimethylethoxy)carbonylbenzoyl]-L-valyl-N-l1-(2-benzoxazolyl)carbonyl-2-methylprop-yl]-L-prolinamide (Formula IV, heterocycle con-taining X, N and Q=2-benzoxazolyl, R7.L.A=4-t(CH3~3COCO]C6H4CO).

t-Butyl alcohol (0.030 ml) was added to a solution of the product of Example 3a (200 mg) and Dess-Martin periodinane (410 mg) in methylene chloride (5 ml) and the solution stirred at room temperature for 16 hr. The resulting solution was partitioned between ethyl acetate and 1:1 saturated Na2S203:~aHC03. The organic phase was separated and washed with 1:1 saturated Na2S203:NaHC03 (twice) and brine~ dried [K~CO3:Na2SO4 (1:2, w:w)] and evaporated. The crude product was purified by flash chromatography, eluting with acetone:hexanes (1:3) to afford the product ~161 mg, 80%) as a solid; TLC, ; Rf=0.35, acetone:hexanes (1:3); HPLC, tR-7~86, Col A, FR-2, water:acetonitrile (40:60); MS, m/e=619 (M+l), ;~ 563, 316, 304, 204, 120, 115.
Analysis for C34H42N47 0~4 H2O
Calculated: C, 65.24; H, 6.89; ~, 8.95 Found: C, 65.26; H, 6.74; N, 8.84 c. (4-Carboxybenzoyl)-L-valyl-N-11-~2-benzoxazol-yl)carbonyl-2-methylpropyl]-L-prolinamide (For-mula IV, heterocycle containing X, N and Q=2-benzoxazolyl, R7.L.A-4-(HooC)C6H4Co).
A solution of the product of Example 3b (770 mg) in trifluoroacetic acid (5 ml) was stirred at roo~ temperature for 2 hr. The solvent was then evaporated. The residual oil was diluted with ether and the resulting solution was evaporated. This ` process was repeated 6 times. The brown oil was then ` placed u~der high vacuum for 48 hr. The crude acid :

-41- 132~ ~7 (now a foam) was purified by flash chromatography, eluting with acetone:hexane:acetic acid (40:60:1) to afford the product (680 mg, 96%) as a yellow solid;
TLC, Rf=0.23, acetone:hexanes:acetic acid ~:6:1 drop/ml); MS, m/e=563 (N~l), 545, 316, 298, 248, 245, 220, 204, 149, 148, 120.
Analysis for C30H34N4O7Ø2 NaOHØ55 H2O:
Calculated: C, 62.07; H, 6.13; N, 9.65 Found: C, 61.70, H, 5.95; N, 9.92 d. [4-~Methylsufonylaminocarbonyl)benzoyl]-L-valyl-~-11-(2-benzoxazolyl)carbonyl-2-methylpropyl~-L-prolinamide (Formula I, heterocycle containing X, N and Q=2-benzoxazolyl, A=CO, L=~-phenylene, R4=R5.S(o2).NH.Co-, R5=CH3).

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (78 mg) was added to a solution of the product of ExamPle 3c (200 mg), 4-dimethylaminopyri-dine (58 mg), and methanesulfonamide (37 mg) inmethylene chloride (2 ml), and the solution stirred at room temperature for 16 hr. After the solvents were evaporated, the residue was partitioned between ethyl acetate and lN HCl~ The organic layer was separated, washed with lN HCl, dried (NgSO4~ and evaporated. The crude product was purified by flash chromatography, eluting with ethyl acetate:ether:acetic acid (20:80:1) to afford the product (74.2 mg, 32%) as a solid; TLC, Rf'0.10, ether:acetic acid (100:1); HPLC, tR-6~03, Col B, FR-2, water:acetonitrile:tetrahydrofuran:
trifluoroacteic acid (55:35:13:0.1); MS, m/e=640 - (M+l), 622, 326, 325, 316, 298, 247, 201.
AnalysiS for C31~37N58S--8 CH3C2H
Calculated: C, 56.93; H, 5,89; N, 10~18 35Found: C, 57~22; H, 5~97; N, 9.79 .

.. . .
- . : .

-42- 13261~7 Example 3 (S)-[4-(Phenylsulfonylaminocarbonyl)benzoyl]-L-valyl-N-[1-(2-benzoxazolyl)carboryl-2-methylpropyl]-L-pro-linamide (Formula I, heterocycle containing X, N andQ=2-benzoxazolyl, A=CO, L=~-phenylene, R4=R5.S(o2).-NH.CO-, R5=C6H5).

a. 4-(Phenylsulfonylaminocarbonyl)benzoic acid.

Using similar procedures to those described in Example 1 parts n and o, except using benzenesul-fonamide in place of 4-chlorobenzenesulfonamide, the benzoic acid was obtained as a solid; mp 259-261.

b. (lS)-14-(Phenylsulfonylaminocarbonyl)benzoyl]-L-valyl-N-11-(2-benzoxazolyl)hydroxymethyl-2-methylpropyl]-L-prolinamide (Formula III, hetero-cycle containing X, N and Q=2-benzoxazolyl, A=CO, L=~-phenylene, R4-R5.S(O2).NH.CO-, R5=C6H5).

1-(3-Dimethylaminopropyl)-3-ethylcarbodi-imide hydrochloride (140 mg) was added to a solution of the product of Example lk (290 mg), l-hydroxy-benzotriazole (200 mg), and 4-(phenylsulfonyl-aminocarbonyl)benzoic acid (179 mg) in tetrahydro-furan ~4 ml); and the solution stirred at room tem-perature for 16 hr. The mixture was partitioned between water and ethyl acetate. The organic phase was washed with saturated NaHCO3 (3 times) and brine, dried (MgSO4) and evaporated. The aqueous layers were combined, acidified to pH 1 with concentrated HCl, and extracted with chloroform. The chloroform phase was dried lK2CO3:Na2S04 (1:2, w:w)] and evaporated.
The crude product obtained from both the ethyl acetate and chloroform solutions was combined and purified by .

~43~ 1 3 2 6~ 07 flash chromatography, eluting with acetone:hexanes:
acetic acid (45:55:1), to afford the product (270 mg, 60X) as a solid; Rf=0.15, acetone:hexane:acetic acid (30:70:1 drop/ml); MS, m/e=704 (M~l), 686, 387, 346, 318, 316, 300, 158, 120.
Analysis for C36H41N58S~~8 C~3C2H
Calculated: C, 58.79; H, 6.03; N, 9.07 Found: C, 59.11; H, 6.02; ~, 8.68 10 c. (S)-14-(Phenylsulfonylaminocarbonyl)benzoyl]-L-valyl-N-[1-(2-benzoxazolyl)carbonyl-2-methyl-propyl~-L-prolinamide (Formula I, heterocycle containing X, N and Q=2-benzoxazolyl, A=CO, L=~-phenylene, R4=R5.S(O2).NH.CO-, R5=C6H5).
Trifluoroacetic acid (0.09 ml~ was added to a solution of the product of Example 4b (270 mg) and Dess-Martin periodinane (490 mg) in methylene ;~ chloride (5 ml) and the solution stirred at room temperature for 16 hr. The resulting solution was diluted with ethyl acetate and washed (4 times with 4:1 brine:saturated Na2S2O3:Na2HCO3 (1:1), once with brine), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography~ eluting with acetone:hexanes:acetic acid (40:60:1). The solid obtained from this column was further purified by flash chromatography on acidic silica gel eluting with chloroform to afford the title compound (152 mg, ` 57~) as a solid; TLC, Rf~0.23, acetone:hexanes:acetic . 30 acid (40:60:1); HPLC, tR~10.09, Col B, FR=2, water:
acetonitrile:tetrahydrofuran:trifluoracetic acid (55:35:15:0.1); MS, m/e=702 (M~l), 326, 299, 298, 297, 201, 136.

~`

, ~ . . . . ~
.,, .
:` :
,- . ..
:

~ -44- 13261~7 Analysis for C36H39N5O8SØ75 NaOHØ25 H2O:
Calculated: C,58.72; H,5.51; N,9.51 Found: C,58.38; H,5.34; N,9.28 Example 4 (S)-14-E(4-Chlorophenyl)sulfonylaminocarbonyl~benzo-- yll-L-valyl-N-~1-(5-methoxybenzoxazol-2-yl)carbonyl-2-methylpropyl]-L-prolinamide (Formula I, heterocycle containing X, N and Q=5-methoxybenzoxazol-2-yl, A=CO, L=~-phenylene, R4=R5.S(O2).NH.CO-, R5=4-ClC6H4).

~- a. ~lS)-Benz~loxycarbonyl-L-valyl-~-[l-(cyanohydroxy-methyl)-2-methylpropyl]-L-prolinamide (Formula XIIl, WSCN).

An alternative, preferred procedure for preparaeion of the product of Example li is as follows: A 250 ml round bottom flask with stirrer was dried under vacuum and purged with nitrogen. The flask was charged with dichloromeehane (120 ml) followed by the addition of aldehyde prepared as described in Example lh (17.7 g) and triethyl amine (3.4 ml). Acetone cyanohydrin (11.0 ml) was added in one portion. The reaction mixture was stirred for 21 hr. The crude reaction mixture was diluted with ` dichloromethane. This solution was carefully washed (twice with saturated ammonium chloride, once with brine), dried (MgSO4), and the solvent evaporated.
The crude product was dissolved in ethyl acetate, ~` washed (once with saturated ammonium chloride, once with brine), dried (MgSO4), and evaporated. The ` resulting foam was heated to 50 under vacuum for four "` 35 days to afford lB.90 g (100%) of product: TLC, Rf=0.31, acetone:hexanes (40:60).
:.

,., :
-~45- 132~1~7 b. (lS)-Benzyloxycarbonyl-L-valyl-N-13-ethoxy-2-hy-droxy-3-imino-1-(1-methylethyl)propyl]-L-prolin-amide hydrochloride (FormNla XIII, W=C(NH)OR, R C2H5).

To a stirred solution of ethanol (79.4 ml) in chloroform (80 ml) at 0 under nitrogen was added dropwise acetyl chloride (87.7 ml) over the course of 25 min. The product of Example 4a (18.81 g) in chlorofonm ~80 ml) was added and the reaction stirred at 0 for 4 h~. The solvents were evaporated to afford the product ~20.89 g); TLC, after partitioning an ali~uot between ethyl acetate and ~N NaOH to form the free imino ether, ~f=0~45~ methanol:chloroform t7.5:92.5).

c. 2-Amino-4-methoxyphenol.

A mixture of 10% (w/w) palladium on carbon (200 mg) and 4-methoxy-2-nitrophenol ~3.0 g) in ethanol (100 ml) was hydrogenated in a shaker at 3.4 bar for 24 hr. The mixture was filtered through diatomaceous earth and evaporated to give the product (2.3 g); TLC, Rf'0.61, methanol:chloroform (1:9); MS, m/e~170(M+1), 164, 152(base), 124.

`~ d. (lS)-Benzyloxycarbonyl-L-valyl-N-ll-(hydroxy)-~5-`~ methoxybenzoxazol-2-yl)methyl-2-methylpropyl]-L-prolinamide (Formula XIV, heterocyle containing X, N and Q~5-methoxybenzoxazol-2-yl).
.
-` A stirred solution of the im~date of Example 4b (6.35 g) and 2-amino-4-methoxyphenol (1.525 g) in dry ethanol (40 ml) was heated for 8 hr at 60 under nitrogen. The mixture was dissolved in ethyl '- acetate, washed (lN HCl, saturated sodium bicarbonate, .

.
.; ; ` ~ , : - , ~, .: ; .,, -46- 1326~07 brine), dried (lOZ (w/w) K2C03/Na2S04), and evaporated.
The crude product was flash chromatographed eluting with acetone:hexanes (30:70) to afford the product (983 mg). The mixed fractions were combined, evaporated and flash chromatographed eluting w~th acetone:hexsnes (35:65) to afford additional product (588 mg); TLC, Rf=0.28, acetone:hexanes (40:60); MS, m/e=582(M+2), 581(M+1), 563, 473, 331, 261, 195, 107, 91, 79, 70.

e. (lS)-L-Valyl-N-ll-(hydroxy)(5-methoxybenzoxazol-2-yl)methyl-2-methylpropyl]-L-prolinamide (For-mula XV, heterocyle containing X, N and Q=5-methoxybenzoxazol-2-yl).

A mixture of 10~ (w/w) palladium on carbon ~300 mg) and the product from Example 4d (1.54 g) in ethanol (100 ml) was hydrogenated in a shaker at 3.4 bar for 4 hr, after which time the mixture was filt-ered through diat~maceous earth and the solvent evaporated. The residue was redissolved in ethanol (100 ml), lOX palladium on carbon (0.69 g) added and the mixture hydrogenated in a shaker at 3.4 bar for 4 hr. The mixture was then filtered through diatomace-ous earth and the solvent evaporated to afford 990 mg (83X) of solid; Rf=O.O, methanol:chloroform (1:19);
MS, m/e=475(M+29), 447(M+1), 429, 348, 234, 233, 197, 180, 179, 178, 155, 150, 100, 72, 70.

~ f. (lS)-[4-[(4-Chlorophenyl)sulfonylaminocarbonyl]-`~ 30 benzoyl]-L-valyl-N-[l-(hydroxy)(5-methoxybenzoxa-zol-2-yl)methyl-2-methylpropyl]-L-prolinamide .
(Formula III, heterocycle containing X, N and Q=
5-methoxyben~oxazol-2-yl, A=CO, L=~-phenylene, R4=R5.S(o2).NH.Co-, R5-4-ClC6H4).

1-(3-Dimethylaminopropyl)-3-ethylcarbodi-imide hydrochloride (470 mg) was added to a solution of the product of Example 4e (990 mg), 1-hydroxybenzo-triazole (330 mg), and the product of Example 1 part o (830 mg) in tetrahydrofuran (7 ml); and the solution was stirred at room temperature for 16 hr. The reaction mixture was then stored at -78 for 36 hr.
The reaction mixture was diluted with ethyl acetate, washed (saturated sodium bicarbonate, lN HCl, brine~, dried tNa2S04), and evaporated~ The resulting solid was redissolved in ethyl acetate, washed (saturated sodium bicarbonate, lN HCl, brine), dried (Na2S04), and evaporated. The crude product was purified by flash chromatography eluting with acetone:chloroform:-acetic acid (20:80:1) to afford the product (976 mg) as a solid; TLC, R~=0.25, acetone:chloroform:acetic acid (35:65:1); MS, m/e=768(N~1), 752, 751, 750, 423, 422, 421, 40~, 377, 348, 330.
~nalysis for C37H42ClN509S.1 8 CH3C02H:
Calculated: C, 55.97; H~ 5.63; N, 8.16 Found: C, 56.14; H, 5.76; N, 7.95 g. (S)-[4-1(4-Chlorophenyl)sulfonylaminocarbonyl]-ben~oyl]-L-valyl-N-[1-(5-methoxybenzoxazol-2-yl)-carbonyl-2-methylpropyl~-L-prolinamide (Formula I, ~; heterocycle containing X, N and Q=5-methoxybenzox-'~ azol-2-yl, A=C0, L=p-phenylene, R4=R5.S(o2).NH.-`~ CO-, R5~4-ClC6H4).

t-Butanol (0.116 ml) was added to a solution of the product of Example 4f (947.6 mg) and Dess-Martin periodinane (1.57 g) in dichloromethane (6 ml), and the solution stirred at room temperature for 21 hr. The resulting suspension was diluted with ethyl acetate and wash~ed (twice with 1:1 saturated Na2S203:
saturated NaHC03, once with lN HCl, brine), dried .:

. ,:

;.. ~,. ;, -48- 132~107 (MgSO4) and evaporated. The crude product was puri-fied by flash chromatography eluting with acetone:-hexane:acetic acid (50:50:1) to afford the product t703 mg) as a solid; TLC, Rf=0.47, ethyl acetate:-hexanes:acetic acid (65:35:1); MS, m/e=766(M+1), 750, 749, 748, 422, 421, 329, 3~8, 327, 326, 249, 231.
Analysis for C37H38ClN5OgS~l~l H2O.1.1 3 2 Calculated: C, 55.26; H, 5.51; N, 8.22 Found: C, 55.16; H, 5.20; N, 8.08 Example 5 (S)-14-[(4-Chlorophenyl)sulfonylaminocarbonyl]benzo-yl~-L-valyl-N-[l-t5-hydroxybenzoxazol-2-yl)carbonyl-2-methylpropyl]-L-prolinamide (Formula I, heterocycle containing X, N and ~s5-hydroxybenzoxazol-2-yl, A=CO, L~p-phenylene, R4=R5.Sto2~.NH.Co-, R5=4-ClC6H4)~

Boron tribromide t3.55 ml, l~OM in dichloro-methane) was added to a solution o$ the product of - Example 4g t680 mg) in dichloromethane t5 ml) at 0 and allowed to warm to room temperature. After 3 hours, the reaction mixture was partitioned between ethyl acetate and lN HCl. The ethyl acetate layer was washed tbrine), dried (MgSO4), and evaporated. The crude product was purified by flash chromatography eluting with methanol:chloroform:acetic acid tl:98:1) to give the product t236 mg, 35%) as a yellow solid;
TLC, Rf-0.28, methanol:chloroform:acetic acid t5:94:-l); HPLC, tR=6.75, Col A, FR-3, water:acetonitrile:-tetrahydrofuran:trifluoroacetic acid t55:35:15:0.1);
MS, m/e=752tM+1), 734, 421, 377, 342, 314(bsse)~
Analysis for:C36H38ClN5OgS 0.2 CHC13.0~3 3 1~5 H2O:
Calculated: C, 53~83; H, 5.20; N, 8.53 - Found: C, 53.65; H, 4.96; N, 8.37 ,~

~49~ 13261~7 Example 6 [4-[(4-Chlorophenyl)sulfonylaminocarbonyl]benzoyl]-L-valyl-N-[1-[5-(aminocarbonyl)benzoxazol-2-yl)carbonyl-2-methylpropyl]-L-prolinamide (Forn~lla I, heterocycle containing X, N and Q=5-(aminocarbonyl)benzoxazol-2-yl, A=CO, L=~-phenylene, R4=R5.S(o2).NH.Co-, R5=4-ClC~H4).

a. 3-Amino-4-hydroxybenzamide.

A solution of 3-amino-4-hydroxybenzoic acid ~7.73 g) in thionyl chloride (96 ml) was stirred vigorously under nitrogen a~ 40 for one hour. The thionyl chloride was removed by distillation under reduced pressure and the resulting solid was suspended in toluene (350 ml). Anhydrous NH3 was bubbled into the reaction mixture for 45 minutes. The mixture was ; 20 filtered through diatomaceous earth and the filter cake was washed copiously with acetone until fresh filtrate was clear. The acetone solution was evapo-rated, and the crude product was flash chromatographed eluting with acetone:chloroform (1:1) to afford the product (1.2 g) as a solid; TLC, Rf=0.17 acetone:-chloroform 160:40); MS, m/e=193(M~41), 181(M+29), 153(M~1), 136, 110.

b~ (lS)-Benzyloxycarbonyl-L-valyl-N-tl-[5-aminocar-bonyl)benzoxazol-2-yllhydroxymethyl-2-methylpro-pyll-L-prolinamide (Formula XIV, heterocycle con-taining X, N and Q=5-(aminocarbonyl)benzoxazol-2-, yl).

. ~
-~ 35 A stirred solution of the imidate of Example 4b (3.81 g) and 3-amino-4-hydroxybenzamide .

-50- ~32~ ~7 (1.00 g) in dry ethanol ~28 ml) was heated for 2 hr at 60 under nitrogen. The mixture was dissolved in ethyl acetate, washed (twice with water, once with ` saturated sodium bicarbonate, brine), dried (MgSO4), -5 and evaporated. The crude product was flash chroma-tographed eluting with acetone:chloroform ~60:40) to afford the product (936 mg); TLC, Rf=0.42, tetrahydro-furan:chloroform (75:25); MS, m/e= 622(M~29), 595(M~2), 594(M~1), 505~ 478, 477.
Analysis for C31H39N57 2 H2O
Calculated: C, 59.13; H, 6.88; N, 11.12 ~ound: C, 59.18; H, 6.35; N, 11.04 c. (lS)-L-Valyl-N-[1-15-(aminocarbonyl)benzoxazol-2-yl3hydroxymethyl-2-methylpropyl]-L-prolinamide (Formula XV, heterocycle containing X, N and Q~5-(aminocarbonyl)benzoxazol-2-yl).

A mixture of 10% (w/w) palladium on carbon (750 mg) and the product from Example 6b (0.920 g) in ethanol (150 ml) was hydrogenated ~n a shaker at 3.4 ~ bar for 4 hr after which time the mixture was filtered "~ through diatomaceous earth and the solvent evaporated.
`~ The residue was then redissolved in methanol and ~'~25 evaporated eo afford the product (680 mg, lOOX) as a solid; TLC Rfs o 0, methanol:chloroform (5:95); MS, m/e~460(M+1), 247, 225, 198, 197, 196, 154, 125, 91.

d. (lS)-[4-[(4-Chlorophenyl)sulfonylaminocarbonyl]-benzoyll-~-valyl-N-[1-[5-(aminocarbonyl)benzoxa-~ zol-2-yl]hydroxymethyl-2-methylpropyl]-L-prolin-;~ amide (Formula III, heterocycle containing X, N
. and Q=5-(aminocarbonyl)benzoxazol-2-yl, A=CO, ;~ L=~-phenylene, R4=R5.S(o2).NH.Co-, R5=4-ClC6H4).
` 35 *? ~r ~

-51- 13261~7 1-(3-Dimethylaminopropyl)-3-ethylcarbodi-imide hydrochloride (292 mg) was added to a solution of the product of Example 6c (670 mg), l-hydroxy-benzotriazole (206 mg), and the product of Example 1 -part o ~507 mg) in tetrahydrofuran (5 ml); and thesolution stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate and washed three times with distilled water, once with lN
HCl, once with saturated sodium bicarbonate, and once with brine. The bicarbonate wash was acidified to pH
1 and extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried (Na2SO4), and evaporated. The crude product was flash chromatographed eluting with tetrahydrofuran:chloro-form:acetic acid (70:30:1). The resulting material was filtered through silica gel eluting with tetrahy-drofuran:chloroform:acetic acid (30:70:0 to 30:70:1 to 100:0:1) to afford the product (350 mg) as a solid;
TLC, Rf=0.55, tetrahydrofuran:chloroform:acetic acid - 20 (80:20:1); MS, m/e-247, 197, 163~

e~ 14-[(4-Chlorophenyl)sulfonylaminocarbonyl~ben-zoyl]-L-valyl-N-11-(5-(aminocarbonyl)benzoxa-zol-2-yl)carbonyl-2-methylpropyl]-L-prolinamide (Formula I, heterocycle containing X, N and ; Qs5-(aminocarbonyl)benzoxazol-2-yl, A=CO, L=~--~ phenylene, R4~R5.S(2) NH.CO-, R5=4-ClC6H4).
. ~
Pyridine (0.422 ml) was added to a sus-`~ 30 pension of chromium trioxide (261 mg) in dry di-` chloromethane (27 ml), and the mixture stirred at room temperature 30 nin. Diatomaceous earth (0.5 g) was added to the mixture which was stirred 5 more min.
The product from Example 6d (340 mg) in dry di-methylformamide (1.5 ml) was added, and the mixture and was allowed to stir for 3.5 hr. The resulting -52- 13261~7 , suspension was filtered through diatomaceous earth and evaporated. The residue was lixiviated with chloro-form and filtered through diatomaceous earth. (The use of methanol for lixiviation is preferred.) This process was repeated six times. The filtrates were combined and evaporated. The resulting solid was flash chromatographed elueing with teerahydro-furan:chloroform:acetic acid (55:45:1). The resulting solid was filtered through silica gel, eluting first with chloroform then with tetrahydrofuran:acetic acid (99:1). The resulting solid was again flash chroma-tographed eluting with tetrahydrofursn:hexanes:acetic acid (60:40:1) to afford the product (37.5 mg); TLC, Rf=0.50, methanol:chloroform:acetic acid (10:90:1);
HPLC, tR=7.23, Col A, FR=l, water:acetonitrile:tètra-hydrofuran:trifluoroacetic acid (55:35:15:0.1); MS, ~/e=777(M~1), 761, 421, 342, 341, 340, 339, 192.
Analysis for C37H39ClN609S 0 90 H20.1 3 2 Calculated: C, 54.75; H, 5.28; N, 9.82 Found: C, 55.07; H, 5.41; N, g.57 Example 7 t4-[(4-Chlorophenyl)sulfonylaminocarbonyl]benzoyl]-L-valyl-N-[1-[5-(hydroxymethyl)benzoxazol-2-yl]car-bonyl-2-methylpropyl]-L-prolinamide (Formula I, heterocycle containing X, N and Q=5-(hydroxymethyl)-benzoxazol-2-yl, A=C0, L-~-phenylene, R4'R5.S(o2).-NH.C0-, R5=4-ClC6H4).

_ ` a. 3-Amino-4-hydroxybenzyl alcohol.

A mixture of 10% (w/w) palladium on carbon (5.25 g) and 4-hydroxy-3-nitrobenzyl alcohol (25.0 g) in ethanol (1.3 liter) was hydrogenated in a shaker at ~326107 3.4 bar for 23 hr, after which time the mixture was filtered through diatomaceous earth and evaporated.
The residue was flash chromatographed, eluting with methanol:chloroform (O:100 to 10:90), to afford the product (11.92 g, 60X) as a red solid; TLC, Rf=0.14, methanol:chloroform (5:95); MS, m/e=140(M+1), 139, 138, 1~3, 122, 110.

b. (lS)-Benzyloxycarbonyl-L-valyl-N-[l-(hydroxy)[5-(hydroxymethyl)benzoxazol-2-yl3methyl-2-methyl-propyl]-L-prolinamide (Formula XIV, heterocycle containing X, N, and Q=5-(hydroxymethyl)benzoxa-zol-2-yl).

`~ 15 The product from Example 4b (3.0 g) and alcohol prepared according to Example 7a (0.771 g) in absolute ethanol (20 ml) were heated at 65 for 20 hr; the mixture was dissolved in ethyl acetate, washed (lN NaOH, brine), dried (MgSO4), and evaporated. The crude product was flash chromatographed eluting with acetone:hexanes (55:45) to give the product (858 mg) `. as a white solid TLC, Rf~0.26, acetone:hexanes (3:2);
`~ _ MS, mle=581(M+1), 563, 501, 473, 455.
~ Analysis for C31H40N47'1'25 H2O:
`~ 25 Calculated: C, 61.73; H, 7.10; N, 9.29 Found: C, 61.81; H, 6.86; N, 9.09 , ` c. (lS)-Benzyloxycarbonyl-L-valyl-N-[1-[5-[(t-butyl-dimethylsilyloxy)methyl]benzoxazol-2-yl](hydroxy) methyl-2-methylpropyl]-L-prolinamide (Formula XIV, heterocycle containing X`, N and Q=5-[(t-butyldi-methylsilyloxy)methyl]benzoxazol-2-yl).

A solution of the product of Example 7b (736 mg), t-butyldimethylsilyl chloride (380 mg), 4-dimethyl-aminopyridine (7.8 mg), and triethylamine (0.37 ml) in ~ B

dichloromethane (10 ml) was stirred at room temper-ature for 16 hr. The solution was then dissolved in ethyl acetate, washed (lN HCl, saturated sodium bicar-bonate, brine), dried (MgS04), and evaporated. The crude product was purified by flash c~r~matography, eluting with acetone:hexanes (1:3), to afford the product (715 mg, 82~) as a light yellow solid; TLC, Rf=0.46, acetone:hexanes (2:3); MS, m~e~695(M+1), 679, 587, 563, 455.
Analysis for C37H54N4O7Si 0~25 H2O
Calculated: C, 63.54; H, 7.85; N, ~.01 Found: C, 63.44; ~, 7.75; N, ~.54 d. (S)-Benzyloxycarbonyl-L-valyl-N-tl-l5-l(t-butyldi-methylsilyloxy)methyl]benzoxazol-2-yl]carbonyl-2-~ methylpropyl]-L-prolinamide (FormDla VI, hetero-;; cycle containing X, N and ~=5-[(t-butyldimethyl-silyloxy)methyl]benzoxazol-2-yl).

~0 Tert-butyl alcohol (0.068 ml~ was added to a so~ution of the product of Example 7c ~500 mg) and Dess-Martin periodinane (1.22 g) in d~chloromethane (5 - ml) and the solution stirred at room *Emperature for 16 hr. The resulting suspension was part~tioned between ethyl acetate and a 1:1 solution of saturated Na2S2O3:saturated NaHCO3; the layers were separated;
and the ethyl acetate layer washed (once with a 1:1 solution of saturated Na2S2O3:saturated NaHCO3, twice with saturated NaHCO3, once with brine3, dried ~MgSO4), and evaporated. The crude product was purified by flash chromatography eluting with acetone:hexanes (1:3) to afford the product (448 mg, 90~) as a white solid; TLC, Rf=0.54, acetone:hexanes (2:3); HPLC, tR=6.18, Col A, FR=2, water:acetonitrile (1:9); MS, m/e=603(M+l, base), 677, 635, 585, 460.

1326~ ~7 Analysis for C37H52N4O7SiØ25 H2O
Calculated: C, ~3.72; H, 7.59; N, 8.03 Found: C, 63.84; H, 7.45: N, 7.70 e. Benzyloxycarbonyl-L-valyl-N-[1-~5-(hydroxymethyl)-benzoxazol-2-yllcarbonyl-2-methylpropyl]-L-prolin-am~de ~FormNla VI, he~erocycle containing X, N and Q=5-~hydroxymethyl)benzoxazol-2-yl).

`` 10 Tetrabutyla~monium fluoride (1.2 ml of lM
`~ solution in tetrahydrofuran) was addèd to a solution ` of the product of Example 7d (418 mg) in tetrahydro-furan (5 ml). The resulting red solution was stirred at room temperature for 10 min and stored at 5 for 16 hr. The red solution was partitioned between ethyl `` acetate and lN HCl, and the ethyl acetate layer was wsshed (saturated sodium bicarbonate, brine), dried (MgSO4), and evaporated. The crude product was purified by flash chromatography elueing with ~ 20 acetone:hexanes ~35:65) followed by a second purifi-`` cation by flash chromatography eluting with methanol:-chlorofonm (2.5:97.5) to afford the product (183 mg, ~ 53~) as a white solid; TLC, Rf=0.52, acetone:hexanes ;~ ~3:2); HPLC, tR-6.27, Col A, FR=l, water:acetonitrile (40:60~; MS, m/e=579(M+1), 561, 331, 225, 197, ~ 91~base).
`; Analysis for C31H38N47 1' H2O:
- Calculated: C, 62.40; H, 6.76; N, 9.39 ~ound: C, 62.23; H, 6.40; N, 9.14 f. [4-r(4-Chlorophenyl)sulfonylaminocarbonyl]ben-zoyl]-L-valyl-N-[1-[5-(hydroxymethyl)benzoxa-zol-2-yl]carbonyl-2-methylpropyl~-L-prolinamide (Formula I, heterocycle containing X, N and Q~5-(hydroxymethyl)benzoxazol-2-yl, A=CO, L=~-phenylene, R4'R5.S(o2).-NH.Co-, R5=4-ClC6H4).

-56- 1 3 2 6~ ~ 7 Trifluoromethanesulfonic acid (0.140 ml) was added to a solution of material prepared according to the procedure of Example 7e (182 mg) in dichlorometh-ane (8 ml), stirred for 15 min, and evaporated. The residue was dissolved in tetrahydrofuran (10 ml) and treated with 4-dimethylaminopyridine (293 mg), the product of Example 1 part o (113 mg), and 1-(3-di-methylaminopropyl)-3-ethyl carbodiimide hydrochloride (66.5 mg), and stirred at room temperature for 16 hr.
The mixture was partitioned between lN HCl and ethyl acetate; the ethyl acetate phase was washed (lN HCl, brine), dried (MgSO4), and evaporated. The crude product was purified by flash chromatography eluting with methanol:chloroform:acetic acid (1.5:97.5:1.0) to afford the product ~77 mg, 32X) as a light yellow solid; TLC, RfS0.28, methanol:chloroform:acetic acid (5:94:1); MS, m/e=766tN+1), 758, 592, 562, 421, 346, 328.
Analysis for C3~H40ClN5OgS~1~0 H2O.1.0 CH3COOH:
~- 20 Calculated: C, 55.48; H, 5.49; N, 8.29 ` Found: C, 55.42; ~, 5.33; N, 8.77 Example 8 (S)-t4-[(4-Chlorophenyl)sulfonylaminocarbonyl]benzo-yl~-L-valyl-N-[1-15-(methoxycarbonyl)benzoxazol-2-yl~carbonyl-2-methylpropyl~-L-prolinamide (Formula I, heterocycle containing X, N and Q-5-(methoxycarbonyl)-benzoxazol-2-yl, A=CO, L=~-phenylene, R4=R5.S(o2).NH.-CO-, R ~4-ClC6H4).
_ _ _ _ ~57~ 13261~7 a. (lS)-Benzyloxycarbonyl-L-valyl-N-~l-(hydroxy)[5-(methoxycarbonyl)benzoxazol-2-yl]methyl-2-methyl-`~ propyl~-L-prolinamide (Formula XIV, heterocycle containing X, N and Q=5-(methoxycarbonyl)benzoxa-zol-2-yl).

A stirred solution of the imidate of Example 4b (5.47 g) and 4-carbomethoxy-2-aminophenol (5.10 g) in dry ethanol (50 ml) was heated for 3 hr at 60 under nitrogen. The mixture was dissolved in ethyl acetate, washed (lN HCl, lN NaOH three times, brine), dried (MgSO4), and evaporated The crude product was flash chromatographed, eluting with acetone:hexanes (30:70), to afford 2.210 g of the product; TLC, Rf=0.18, acetone:hexanes (35:65); MS, 649(M~41), 637(M~29), 611(M+3), 610(M+2), 609(M+l), ~ 591, 501.
`` Analysis for C32H40N4O8 0 35 CH3CO2 2 5 '5 Calculated: C, 62.73; H, 6.74; N, 8.76 Found: C, 62.71; H, 6.73; N, 8.67 ` b. (S)-Benzyloxycarbonyl-L-valyl-N-[1-[5-(meehoxy-_ car~Qnyl)benzoxazol-2-yl]carbonyl-2-methylpropyl]-L-prolinamide (Formula VI, heterocycle containing X, N and Q=5-(methoxycarbonyl)benzoxazal-2-yl).

e-Butanol (0.340 ml) was added to a solution of the product of Example 8a (2.70 g) and Dess-Martin periodinane (4.62 g) in dichloromethane ~20 ml) and the solution stirred at room temperature for 22 hr.
The resulting suspension was diluted with ethyl acetate and was washed (three portions of 1:1 saturat-ed Na2S2O3:saturated NaHCO3, brine), dried (MgSO4), - and evaporated. The crude product was purified by flash chromatography eluting with acetone:hexane (25:75) to afford 2.20 g of solid; TLC, Rf=0.21, ~3 aceeone:hexanes (30:70); MS, m/e=635(M~29), 608(M+2), 607(M+1), 374, 331, 91.
Analysis for C32H38N4O8-0-5 2 Calculated: C, 62.43; H, 6.38; N, 9.10 Found: C, 62.43; H, 6.24; N, 8.91 c. (S)-L-Valyl-N-[1-I5-(methoxycarbonyl)benzoxazol-2-yllcarbonyl-2-methylpropyl]-L-prolinamide (Formula V, heterocycle containing X, N and Q-5-(methoxycarbonyl~benzoxazol-2-yl).

To a stirred solution of the product of `~ Example 8b (500 mg) in dichloromethane (4 ml) under nitrogen was added trifluoromethanesulfonic acid (0.365 ml) dropwise. After 5 min the reaction mixture was poured into distilled water (100 ml~ and was extracted three t~mes with dichloromethane. The aqueous layer was adjusted to pH 8 with NaHCO3 and `~ washed three times with dichloromethane. The aq~eous phase was treated with lN NaOH (50 ml) and washed once more with dichloromethane. The organic washes were - co~bined, dried (Na2S04), and evaporated to afford 185 mg (48~) of a white foam~ TLC, Rf=0.22, methanol:-chloroform (5:95).
d. (S)-[4-[(4-Chlorophenyl)sulfonylaminocarbonyl]-benzoyll-L-valyl-N-~1-[5-(methoxycarbonyl)benzoxa-zol-2-yllcarbonyl-2-methylpropyl]-L-prolinamide (Formula 1, heterocycle containing X, N and Q=5-Imethoxycarbonyl)benzoxazol-2-yl, A-CO, L~ phen-ylene, R4-R5.S(o2).NH.Co-, R5-4-ClC6H4).
.
1-(3-Dimethylaminopropyl)-3-ethylcarbodi-imide hydrochloride (160 mg) was added to a solution of the product of Example 8c (185 mg), l-hydroxy-benzotriazole (110 mg), and the product of . .
.. .; ,.
.

_59- 1326107 Example 1 part o (280 mg) in tetrahydTofuran (3 ml) and the solution stirred at room temperature f~r 16 hr. The reaction mixture was diluted with ethyl acetate, washed (three times with lN HCl, brine), dried (MgSO4), and evaporated. The crude product was purified by flash chromatography eluting with ace-tone:dichloromethane:acetic acid (20:80:1 drop/ml) to af~ord 160 mg of solid: Rf=0~36, methanol:chloroform:-acetic acid (5:95:1 drop/ml); HPLC, tR=15.84, Col A, ; 10 water:acetonitrile:tetrahydrofuran:trifluoroacetic acid (55:35:15:0.1), FR=2 MS, m/es684(M~29), 656(M+l), 375, 374, 356, 355, 354, 352, 302, 283, 260, 259, 178, 168.
Analysis for C38H40ClN5OloS~l~o H2O 1 3 2 - 15 Cal~ulated: C, 55.07; H, 5.31; N, 8.03 Found: C, 55.05; H, 5.13; N, 8.06 Example 9 (S)-14-[(4-Chlorophenyl)sulfonylaminocarbonyl]ben-zoyll-L-valyl-N-[1-[6-(methoxycarbonyl)benzoxazol-2-yllcarbonyl-2-methylpropyl]-L-prolinamide (Formula I, heterocycle containing X, N and Q=6-(methoxycarbonyl)-benzoxazol-2-yl, A=CO, L=~-phenylene, R4=R5.S(o2).NH.-CO-, R =4-ClC6H4).

a. (lS)-Benzyloxycarbonyl-L-valyl-N-[1-(hydroxy)-[6-(methoxycarbonyl)benzoxazol-2-yl]methyl-2-methylpropyl]-L-prolinamide (Formula XIV, hetero-cycle containing X, N and Q=6-(methoxycarbonyl)-benzoxazol-2-yl).

... .

.

13~61~7 A stirred solution of imidate prepared as described in Example 4b (1.00 g) and 5-carbomethoxy-2-aminophenol (930 mg) in dry ethanol (9 ml) was heated for 4 hr at 60 under nitrogen. The mixture was dissolved in ethyl acetate, washed (twice with lN
NaOH, brine), dried (MgSO4) and evaporated. The crude product was flash chromatographed, eluting with acetone:hexanes (35:65), to afford 300 mg of the product; TLC, Rf=0.50, acetone:hexanes (45:55); MS, m~e=610(M+2), 609(M+l).

b. (S)-Benzyloxycarbonyl-L-valyl-N-[1-[6-(methoxy-carbonyl)benzoxazol-2-yl]carbonyl-2-methylpro-pyl]-L-prolinamide (Formula VI, heterocycle con-taining X, N and Q=6-(methoxycarbonyl)benzoxa-zol-2-yl).

t-Butanol (0.050 ml) was added to a solution of the product of Example 9a, (3Q0 mg) and Dess-Martin periodinane (630 mg) in dichloromethane (3 ml) and the solution stirred at room temperature for 17 hr. The resulting suspension was diluted with ethyl acetate and was washed (three portions of 1:1 saturated Na2S203:NaHC03, brine), dried (MgSO4) and èvaporated.
The crude product was purified by flash ~hromato-graphy, eluting with acetone:hexane (30:70~, to afford a solid which was dissolved in acetonitrile (30 ml) and treated with 300 mg of activated charcoal. The mixture was stirred for 10 min, filtered and evapo-rated to afford 257 mg of the product; TLC, Rf =0.49, `; acetone:hexanes (40:60); MS, m/e=635(M+29), 608(M+2), 607(M+l)~.
Analysis for C32H38N4O8Ø5 H2O
Calculated: C, 62.43: H, 6.38; N, 9.10 Found: C, 62.62; H, 6.28; N, 8.94 . ::

c. tS)-L-Valyl-N-[1-l6-(methoxycarbonyl)benzoxazol-2-yl]carbonyl-2-methylpropyl~-L-prolinamide tri-fluoromethanesulfonic acid salt (Formula V, heterocycle containing X, N and Q=6-(methoxycar-bonyl)benzoxazol-2-yl).
-To a stirred solution of the product of Example 9b, ~21Q m~) in dichloromethane (1.5 ml) under nitrogen was added trifluoromethane sulfonic acid ~0.15 ml) dropwise. After 40 min the reaction mixture was evaporated. The resulting solid was placed under vacuum for an hour and used directly in Example 9d, below; TLC, Rf-0.00 acetone:hexanes (25:75); MS, m/e=244, 242, 235, 195, 189, 186, 181, 178, 121, 105, 93, 92, 91, 79.

d. (S)-14-[(4-Chlorophenyl)sulfonylaminocarbonyl]-benzoyl~-L-valyl-N-[1-[6-(methoxycarbonyl)benz-oxazol-2-yl]carbonyl-2-meehylpropyl]-L-prolin-amide (Formula 1, heterocycle containing X, N
and Q=6-(methoxycarbonyl)benzoxazol-2-yl, A=CO, `~ L=~-phenylene, R4-R5.S(o2).NH.Co-, R5=4-ClC6H4).

1-(3-Dimethylaminopropyl)-3-ethylcarbodi-imide hydrochloride (75 mg) was added to a solution of the product of Example 9c, above, l-hydroxybenzotri-azole (50 mg) and 4-1(4-chlorophenyl)sulfonylamino-` carbonyl3benzoic acid (130 mg) in methylene chloride (2 ml) and tetrahydrofuran (2 ml) followed by the addition of 4-methylmorpholine (0.041 ml) and the solution stirred at room temperatuse for 16 hr.
Additional 4-methylmorpholine (0.041 ml) was added to the reaction mixture and the reaction stirred an additional 7 hr. The reaction mixture was diluted 7' 35 with ethyl acetate, washed (lN HCl (three times), brine), dried (MgSO4), and evaporated. The crude . _ .. , . . . . . _.
.

.
" : :
~. . .

. .

- -62- 1326~07 product was purified by flash chromatography, eluting with acetone:methylene chloride:acetic acid (30:70:1), to afford of a solid (160 mg) which was further purified by flash chromatography, using a gradient elution of acetone:methylene chloride:acetic acid (500 ; ml of 0:100:1; 900 ml of 10;90:1; then 50:50:1), to afford the title compound (71.6 mg); TLC, Rf=0.17, acetone:chloroform:acetic acid (10:90:1); HPLC, tR-15.84, Col A, FR=2, water:acetonitrile:tetrahydro-furan:trifluoroacetic acid (~5:35:15:0.1); MS, m/e=794(M~1), 778, 777, 776, 423, 422, 421, 384, 374, 3~7, 3~6, 355, 354, 259.
Analysis for C38H40ClN5OloS~1 0 H~0~1.5 CH3CO2H:
Calculated: C, 54.57; H, 5.36; N, 7.76.
Found: C, 54.34; H, 5.19; ~, 7.81.

Example 10 (S)-[4-[(4-Chlorophenyl)sulfonylaminocarbonyl]benzo-yl-L-valyl-N-[1-~5-carboxybenzoxazol-2-yl)carbonyl-2-methylpropyl~-L-prolinamide (Formula I, heterocycle containing X, N and Q=5-carboxybenzoxazol-2-yl, A=CO, L=~-phenylene, R4-R5.S(o2).NH.Co-, R5=4-ClC6H4).

a. (lS)-Benzyloxycarbonyl-L-valyl-N-tl-(5-carboxy-benzoxazol-2-yl)hydroxymethyl-2-methylpropyl]-L-prolinamide (Formula XIV, heterocycle contain-ing X, N and Q~5-carboxybenzoxazol-2-yl).
A stirred solution of imidate prepared as in Example 4b (3.00 g) and 3-amino-4-hydroxybenzoic acid (2.55 g) in dry ethanol (25 ml) was heated for 1.5 hr at 60 under nitrogen, after which time an additional amount of imidate (2.00 g) and amino phenol (1.85 g) were added. The mixture was heated an additional 8.25 :``

:
::

,,; ' ' . ::, ' ; , , , ' : ~,. .,:
..

hr. The mixture was dissolved in ethyl acetate, washed (lN HCl (twice), brine), dried (MgS04) and evaporated. The crude product was flash chromato-graphed, eluting with acetone:hexanes:acetic acid (50:50:1), to afford the product (330 mg); TLC, Rf=0.1~, acetone:hexanes:acetic acid (50:50:1); MS, m/e=5~5(M~1), 577.

b. (l~)-L-Valyl-N-11-(5-carboxybenzoxazol-2-yl)-hydroxymethyl-2-methylpropyl)-L-prolinamide (For-mula XV, heterocycle containing X, N and Q=5-carboxybenzoxazol-2-yl).

A mixture of 10% palladium on carbon (1.50 g) and the product of Example lOa (2.~0 g) in ethanol (100 ml) was hydrogenated in a shaker at 3.4 bar for 3 hr, after which time the mixture was filtered through diatomaceous earth and the solvent evaporated to afford product (1.95 g); TLC, Rf=0.0, methanol:-chloroform:acetic acid (5:95:1); MS, m/e-461(M+l), 443, 331, 319, 290, 265, 248, 232, 225, 198, 197, 196, 154.
.
c. (lS)-[4-~(4-Chlorophenyl)sulfonylaminocar-bonyllben~oyl]-L-valyl-N-[1-(5-carboxybenzoxa-zol-2-yl)hydroxymethyl-2-methylpropyl]-L-prolin-amide (Formula III, heterocycle containing X, N and Qe5-carboxybenzoxazol-2-yl, A=C0, L=p-phenylene, R4=R5.S(o2).NH.Co-, R5=4-ClC6H4).
; 30 Isobutyl chloroformate (0.34 ml) was added dropwise over the course of three min to a stirred, -40 solution of 4-[(4-chlorophenyl)sulfonylamino-carbonyl]benzoic acid (850 mg) and 4-methylmorpholine (0.58 ml) in dry tetrahydrofuran (12 ml). The mixture was stirred for 30 min after which time the product -.
~' ` , . , .

~-, ' ' .
., .

-64- 1 3 2 61 ~7 from Example lOb (800 mg) in dimethylformamide (9 ml) was added dropwise to the reaction mixture. The reaction was allowed to warm slowly to room tempera-ture overnight. The resulting mixture was diluted with ethyl acetate, washed (twice with lN HCl, once with brine), dried (NgSO4), and evaporated. The crude - material was flash chromatographed, eluting with acetone:methylene chloride:acetic acid (30:70:1), to afford the product (570 mg) TLC, Rf~0.28, acetone:
methylene chloride:acetic acid (42:60:1); MS, m/e=782-(M+l), 764, 423, 421,377, 193, 191.

d. (S)-l4-[(4-Chlorophenyl)sulfonylaminocarbonyl]-benzoyl-L-valyl-N-[1-(5-carboxybenzoxazol-2-yl)-carbonyl-2-me~hylpropyl]-L-prolinamide (Formula I, heterocycle containing X, N and Q=5-carboxybenz-oxazol-2-y51, A=CO, L=~-phenylene, R4=R5.S(o2) -NH.CO-, R =4-ClC6H4).

t-Butanol ~0.070 ml) was added to a solution of the product of Example lOc (560 mg) and Dess-Nartin periodinane (910 mg) in dry dichloromethane (3 ml) and the solution stirred at room temperature for 21 hr.
The resulting suspension was diluted with ethyl acetate, washed (half saturated Na2S2O3 (three times)), dried (MgSO4), and evaporated. The crude product was purified by flash chromatography, eluting with acetone:dichloromethane:acetic acid (30:70:1), to afford the title compound (100 mg); TLC, Rf-0.28, methanol:chloroform:acetic acid (5:95:1); MS, m/e-781(M+1), 764, 763, 762, 423, 421, 342, 341; HPLC, tR-10.43, Col A, FR=2, water:acetonitrile:tetrahydro-furan:trifluoroacetic acid ~55:35:15:0.1).
`~ Analysis for C37H38ClN5O8S 0 50 H20.1.50 CH3CO2H:
Calculated: C, 54.64; H, 5.16; N, 7.96.
Found: C, 54.64; H, 5.30; N, 7.73.

,, , . .~ .
: ~ `; , - .

-65- 13261~7 Example 11 - [4-(Isopropylsulfonylaminocarbonyl)benzoyl]-L-valyl-` N-11-(2-benzoxazolyl)carbonyl-2-methylpropyl]-L-prolinamide (FormNla I, heterocycle containing X, N
and Q=2-benzoxazolyl, A=CO, Ls~-phenylene, R4=R5.--' S(2)~NH.CO-, RS=cH(CH3)2)~

a. t-Butyl 4-lisopropylsulfonylaminocarbonyl)-benzoate.

1-(3-Dimethylaminopropyl)-3-ethylcarbodi-imide hydrochloride (198 mg) was added to a stirred mixture of 4-(t-butoxycarbonyl)benzoic acid (195 mg), 2-propanesulfonamide (98 mg) and 4-dimethylamino-pyridine (126 mg) in dichloromethane (3.7 ml). The mixture was stirred overnight, diluted with ethyl `~ acetate, washed (lN HCl, brine), dried (MgSO4), and evaporated. The crude product was purified by flash chromatograpy, eluting with acetone:hexanes (75:25), to afford the product (193 mg); TLC, Rf=0.64, ace-tone:hexanes ~75:25); MS, m/e~356(N+29), 330(M+3), 329(M+2), 328(M+1), 272, 223, 222, 205, 204, 166.
~5 ; b. 4-(Isopropylsulfonylaminocarbonyl)benzoic acid.

. Trifluoroacetic acid t5 ml) was added to the ` product from Example lla (193 mg). The resulting solution was stirred 6.5 hr, then evaporated. The crude material product was redissolved in ether and evaporated ~four times). The crude product was then added to a volume of hexanes and evaporated (twice) to afford of the product (214 mg); TLC, RfS0.29, ace-tone:hexanes:acetic acid (50:50:1); MS, m/e=272(M+l), 166, 148, 115, 109, 95.

:`
; .
~ .
~".~ ~

:. . ~ .. :

' c. [4-(Isopropylsulfonylaminocarbonyl)benzoyl]-L-valyl-N-~1-(2-benzoxazolyl)hydroxymethyl-2-methyl-propyl~-L-prolinamide (Formula III, heterocycle containing X, N and Q=2-benzoxazolyl, R4=R5.-S(O~).NH.CO-, R5=CH(CH3)2).

1-(3-Dimethylaminopropyl)-3-ethylcarbodi-imide hydrochloride (166 mg) was added eo a stirred solution of the product of Example_lk (362 mg), the prod~ct of Example llb (214 mg) and l-hydroxybenzo-triazole (117 mg) in dichloromethane (3 ml), and the mixture stirred overnight. The reaction mixture was diluted with ethyl acetate, washed (lN HCl (three times)), dried (NgSO4), and evaporated. The crude product was purified by flash chromatograpy, eluting with tetrahydrofuran:hexanes:aretic acid (65:35:1) to afford the product (215 mg); TLC, Rf~0.44, acetone:
hexanes:acetic acid (75:25:1); MS, m/e=671(M+2), 670(M~1), 653, 652, 353, 319, 318, 300, 249, 231, 204, 124, 120.

d. 14-(Isopropylsulfonylaminocarbonyl)benzoyl]-L-` valyl-N-1-(2-benzoxazolyl)carbonyl-2-methylpropyl]-` 25 L-prolinamide ~Formula I, heterocycle containing X, N and Qs2-benzoxazolyl, L=~-phenylene, R4-R5.S(O2).NH~SO-, R5~CH(CH3)2).

Dess-Martin periodinane (408 mg) was added to a stirred solution of the product of Example llc (215 mg) and t-butanol (0.09 ml) in dichloromethane (3 ml). The resuleing suspension was stirred overnight.
" The reaction mixture was filtered and the solvent evaporated. The resulting oil was filtered through sillca gel with acetone:hexanes (65:35) to afford 404 mg of the crude product. This crude product was .
`::
, . ' :
..
~ ;;: . . .~ ~

.
'; ':

l326~a7 - purified by flash chromatography eluting with tetrahy-drofuran:hexanes:acetic acid (55:45:1) and the result-ing solid was dissolved in dichloromethane (5 ml) and treated with decolorizing carbon (15 mg). The sus-pension was filtered and the solvent evaporated to afford the product (130 mg); TLC, Rf=0.67, methanol:-chloroform:acetic acid (5:95:1); HPLC, tR=9~50~
Col B, FR=2, water:acetonitrile:tetrahydrofuran:tri-`` fluoroacetic acid (55:35:15:0.1); MS, m/e=696(M~29), 669(M+2), 668(M~1), 651, 650, 353, 317, 316, 309, 299, 298, 297, 296, 201.
Analysis for C33H41N5O8S 0 85 H2O
Calculated: C, 58.02; H, 6.30; N, 10.25 Found: C, 58.29; H, 6.17; N, 9.67 :
Example 12 14-[(4-Chlorophenyl)sulfonylaminocarbonyl]benzoyl3-L-valyl-N-[1-(2-oxazolyl)carbonyl-2-methylpropyl]-L-; prolinamide (Formula I, heterocycle containing X, N
and Q=2-oxazolyl, A=CO, L=~-phenylene, R4=R5.S(02).-~` NH . CO-, R5~4-ClC6H4 ) .

-~ a. 2-Trimethylsilyl oxazole.

n-Butyllithium (28.5 ml of a 2.54 M solution in hexane) was added to a -78 solution of oxazole (5.0 g) in ether (150 ml). The resulting solution was ` stirred at -78 for 30 min, followed by the addition ` of trimethylsilyl chloride (7.86 g), and the mixture allowed to warm to room temperature. The reaction mixture was distilled and the fraction with a boiling point of about 130 was collected to afford 2-tri-.

-.

-68- ~32~

methylsilyl oxazole (5.12 g); MS, m/e=142(M+l), 91, 73.

b. (lS)-Benzyloxycarbonyl-L-valyl-N-[1-(2-oxazolyl)-hydroxymethyl-2-methylpropyl]-L-prolinamide (Formula XIV, heterocycle containing X, N and Q=2-oxazolyl).

A solution of the aldehyde (of formula XI) prepared in a similar manner to that described in Example lh (7.4 g) and the product of Example 12a (4.84 g) in toluene (10 ml) was heated at 80 for 24 hr and at 60 for an additional 14 hr. The solvents were evaporated, and the residue was dissolved in ~etrahydrofuran (50 ml) and treated with lN HCl ~5 ml) and stirred for 30 min. The mixture was dissolved in ethyl acetate, washed (lN HCl, saturated sodium bicarbonate, brine), dried (MgS04), and evaporated.
The crude material was purified by flash chroma-tography, eluting with acetone:hexanes (30:70), to afford the product (4.57 g); TLC, Rf=0.31, methanol:-chloroform (5:95); MS, m/e=501(M~1), 483, 393 Analysis for C26H36N06:
Calculated: C, 62.38; H, 7.25; N, 11.19 Found: C, 62.52; H, 7.22; N, 10.87 c. (S)-Benzyloxycarbonyl-L-valyl-N-[2-methyl-1-[(2-oxazolyl)carbonyl]propyl]-L-prolinamide (Formula - VI, heterocycle coneaining X, N and Q-2-oxazolyl).
t-Butanol (0.83 ml) was added to a solution of the product of Example 12b (4.4 g) and Dess-Martin ; periodinane (15 g) in dichloromethane (150 ml) and stirred for 16 hr. The resulting suspension was partitioned between saturated Na2S203:saturated NaHC03 (1:1) and ethyl acetate. The ethyl acetate :`

.~
~ , .. ,, . . : -~ . . ~. .
: ' . ' , , ' ~,: '., ' ", -- ~

-69- 1 32~07 solution was washed (saturated Na2S2O3:saturated NaHCO3 (1:1), saturated NaHCO3, brine), dried (MgSO4), and evaporated. The residue was purified by flash chromatography, eluting with acetone:hexanes (35:65), to afford 4.8 g solid. This solid was dissolved in - ethyl acetate, washed (saturated Na2S203:saturated NaHCO3 (1:1~, saturated NaHC03, brine), dried (MgSO4), and evaporated to afford the product as a white foam (3,74 g); TLC, Rf=0.32, acetone:hexanes (40:60); MS, 10 m/e=499 (M~l), 266.
~nalysiS for C26H34~46 Calculated: C, 62.64; H, 6.87; N, 11.24 Found: C, 62.30; H, 6.74; N, 11.01 d~ 14-[(4-Chlorophenyl)sulfonylaminocarbonyl]ben-zoyl-L-valyl-N-[1-(2-oxazolyl)carbonyl-2-methyl-propyl~-L-prolinamide (Formula 1, heterocycle containing X, N and Q=2-oxazolyl, L=p-phenylene, R4=R5.S(o2).NH.Co-, R5-4-ClC6H4).
j Trifluoromethanesulphonic acid (0.89 ml) was added to a solution of the product of Example 12c (1.0 g) in dichloromethane (15 ml) and stirred for 10 min, the solvents evaporated and the residue placed under high vacuum for 20 min. The residue was dissolved in ~ ~etrahydrofuran (40 ml) and treated with 1-(3-di-`~ methylaminopropyl)-3-ethylcarbodiimide hydrochloride (429 mg), 4-[(4-chlorophenyl~sulfonylaminocarbonyl]-benzoic acid (800 mg) and 4-dimethylaminopyridine ~` 30 (1.97 g). The mixture was stirred at room temperature for 16 hr, dissolved in ethyl acetate, washed (lN HCl, ` saturated NaHC03, brine), dried (MgSO4), and evapo-rated. The crude material was purified by flash chromatography, eluting with acetone:hexanes:acetic ~ 35 acid (10:90:1 to 20:80:1), to afford the product (930 ; mg); TLC, Rf=0.40, methanol:chloroform:acetic acid : , . .
-- ~: ': . ' .
... ., - ~ .
.-.,~- . .

~70- ~32~1~7 (5:95:1); ~PLC, tR--7~35~ Col A, FR=2, water:ace-tonitrile:tetrahydrofuran:trifluoroacetic acid (55:35:15:0.1); MS, m/e=686(M+1), 668, 393, 377, 266, 248.
Analysis for C32H36clNso8s~o~5 H2'1' CH3COOH
Calcualted: C, 54.07; H, 5.47; N, 9.27.
Found: C, 53.78; H, 5.33; ~, 9.25.

Example 13 t4-1(4-Chlorophenyl)sulfonylaminocarbonyl]benzoyl~-L-valyl-N-tl-t2-benzothiazolyl)carbonyl-2-methyl-propyl]-L-prolinamide (Formula I, heterocycle con-taining X, N and Q=~-benzothiazolyl, A-CO, L=~-phenylene, R4-R5.S(o2).NH.Co-, R5=4-ClC6H4).

a~ Nu-Benzyloxycarbonyl-N-methoxy-N-methylvalin-amide.
`! 20 A solution of 1-(3-dimethylaminopropyl)-` 3-ethylcarbodiimide hydrochloride (19.07 g) in di-chloromethane (500 ml) was cooled to -10. To this solution were added l-hydroxybenzotriazole (13.44 g) ' 25 and 4-methylmorpholine (11.5 ml). A solution of N-(benzyloxycarbonyl)-L-valine (25.0 g) in dichloro-methane (200 ml) was added dropwise to the reaction mixture. Ater addition was complete, the mixture was -~ warmed to ambient temperature and stirred for 0.5 hr before being cooled to 10. A mixture of N-methyl-O-methylhydroxylamine hydrochloride (9.7 g) and 4-methylmorpholine (11.5 ml) in dichloromethane (150 ` ml) was added dropwise to the stirred reaction mix-ture. The reaction was warmed to ambient tempera-ture with overnight stirring. The mixture was evapo-rated and the residue was partitioned between water `:;

~, . .

' ;' ' ~
': . , ' -71- 1 3 2 61 ~ 7 and ethyl acetate. The organic layer was washed (10%
HCl, saturated NaHCO3, brine), dried (MgSO4), evapo-rated and dried overnight under high vacuum to give the product as a gum (26.25 g) which solidified in the freezer; TLC: Rf=0.57, chloroform:methanol (40:1); MS, m/e=295(M+1), 234, 187, 162, 152, 119.

b~ (S)-1-(2-Benzothiazolyl)-2-(benzyloxycarbonyl)-amino-3-methyl-1-butanone.
Dry ether (5 ml) was cooled to -78 and n-butyllithium (6.0 ml of 2~54 M solution in hexanes) was added. A dry ether tl5 ml) solution of benzo-thiazole (1.83 g) was added rapidly dropwise. Stir-ring at -78 was continued for 10 min. An ether (10 ml) solution of amide prepared according to the `, procedure of Example 13a and used without further purification (2.00 g) was added via cannula, and the reaction mixture was allowed to warm to 30 with stirring for 1 hr. The reaction mixture was quenched by pouring into saturated NH4Cl and extracted with ethyl acetate. The extracts were dried (Na2SO4) and evaporated to give a yellow oil. Purification by flash chromatography, eluting with hexane:ethyl acetate (10:1), gave the product as a yellow glass (0.98 g); TLC, RfS0.67, hexane:ethyl acetate (2:1);
MS, m/e~368(N+1), 206, 191, 162, 135, 91 (base).

c. 2-Amino-1-~2-benzothiazolyl)-3-methyl-1-buta-~ 30 none.
:' Material prepared according to the procedure of Example 13b (0.94 g) was dissolved in a mixture of dichloromethane (20 ml) and anisole ~1 ml) under nitrogen. Trifluoromethanesulfonic acid (1 ml) was added and the reaction was stirred for 10 min. The . ... .

~, .

' I) 1326~7 reaction was diluted with dichloromethane and ex-tracted with water. The aqueous extracts were washed with dichloromethane, brought to pH=8 with saturated NaHC03 and extracted with dichloromethane. The organic solution was dried (Na2SO4) and evaporated to give a yellow oil ~0.50 g); TLC, Rf=0.36, hex-ane:ethyl acetate (2:1).

d. Benzyloxycarbonyl-L-valyl-~-11-(2-benzothiazol-yl)carbonyl-2-methylpropyl]-L-prolinamide (For-mula VI, heterocycle containing X, N and Q=2-benzothiazolyl).

A dichloromethane solution of material prepared according to the procedure of Example 13c and used without further purification (0.5 g), 1-hydroxybenzotriazole (0.58 g) and product prepared according to the method of Example lf (0.74 g) was treated with l-t3-dimethylaminopropyl)-3-ethylcar-bodiimide hydrochloride (0.47 g), and the reaction mixture was stirred under nitrogen for 15 hr. The reaction mixture was diluted with dichloromethane, washed (saturated NaHCO3, 10% HCl), tried (Na2SO4) and evaporated to give a yellow oil (1.48 g); TLC, Rf~0.39, chloroform:methanol (50:1): MS, mle=565(M+l, : base), 332, 331.

e. L-Valyl-N-11-(2-benzothiazolyl)carbonyl-2-methylpropyl]-L-prolinamide (Formula V, hetero-cycle containing X, N and Q=2-benzothiazolyl).

Amide prepared according to the procedure of Example 13d and used without further purification (1.20 g) was deprotected using a similar procedure to the procedure of Example 13c to give the product as . ~

_73- 13261~7 an oil (0.34 g, 37%); TLC; Rf=0.34, chloroform:
methanol (10:1).

f. [4-l(4-Chlorophenyl)sulfonylaminocarbonyl]ben-zoyl]-L-valyl-N-11-(2-benzothiazolyl)carbonyl-2-methyl-propyl~-L-prolinamide (Formula I, heterocycle containing X, N and Q=2-benzothia-zolyl, A=CO, Ls~-phenylene, R4-R5.S(o2).NH.Co-, R5=4-ClC6H4 ) .
Amine prepared according to the procedure of Example 13e and used without further purification (0.34 g), l-hydroxybenzotriazole (0.21 g) and 4-[(4-chlorophenyl)sulfonylaminocarbonyl]benzoic acid (0.27 g) were combined in dichloromethane (12 ml) and the suspension was treated with 1-(3^dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.17 g). Stirring was continued for 7.5 hr. The reaction was diluted with ethyl acetate and washed (saturated NaHCO3, lOZ
HCl), dried (Na2SO4) and evaporated to give an oily foam. Purification by flash chromatography, eluting with hexanes:ethyl acetate:acetic acid (50:50:1.5), gave the product as a white solid (0.32 g); TLC, Rf=0.29, hexanes:ethyl acetate:acetic acid (50:50:1.5); HPLC, tR=26, Col A, FR=2, water:aceto-nitrile:tetrahydrofuran:trifluoro acetic acid (55:35:15:0.1) MS, m/e~752(M~1), 423, 421, 393, 377, 342, 332, 315, 314 (base), 313, 312, 136.
AnalysiS for C36H38ClN5O7S2-0-3 3 Calculated: C, 57.07; H, 5.13 N, 9.09 Found: C, 57.32; H, 5.45; N, 8.76 _74_ 1~2~107 Example 14 (S)-~4-~(4-Chlorophenyl)sulfonylaminocarbonyl]ben-zoyll-L-~alyl-N-[2-methyl-1-(2-thiazolyl)carbonyl-propyl~-L-prolinamide (Formula I, heterocycle con-taining X, N and Q=2-thiazolyl, A=CO, L=p-phenylene, R4=R5.S(o2).NH.Co-~ R5=4-ClC6H4).

a. (S)-2-(Benzyloxycarbonyl)amino-3-methyl-1-(2-thiazolyl)-l-~utanone To a cooled (-35) solution of thiazole -~ (1.23 ml) in dry tetrahydrofuran (40 ml) was added n-butyllithium (6.6 ml of a 2.18N solution in hexane) over 3 min. The dark brown reaction mixture was stirred in the temperature range -30 to -25 for 10 mi~. A solution of material prepared according to the procedure of ExamPle 13a and used without further purification (1.7 g) in dry tetrahydrofuran (15 ml) was added rapidly over 1 min. Stirring at -30 was continued for 1~ min. The mixture was quenched by ` pouring it into saturated NH4Cl (100 ml), and the ; organics were extracted into ethyl acetate. The extracts were washed (saturated NaHC03), dried ; (Na2S04) and evaporated to give a brown oil. Puri-fication by flash column chromatography, eluting with hexane:ethyl acetate (2:1), gave the product as a yellow oil (1.81 g, 98Z); TLC, Rf=0.45, hexane:ethyl acetate (2:1); MS, m/e~319(M+l, base), 275.

; b. (S)-2-Amino-3-methyl-1-(2-thiazolyl)-1-butanone.

Ketone prepared according to the procedure of Example 14a ~1.8 g) was dissolved in dichloro-methane (30 ml) and treated with trifluoromethane-:`

', ~ ! ' ' , ' .

sulfonic acid (2.5 ml) in a single portion, and the reaction was stirred at ambient temperature for 5 min.
The mixture was diluted with dichloromethane and extracted with water. The aqueous phase was brought to basic pH with saturated NaHCO3 and then was ex-- tracted with dichloromethane. The extracts were dried (Na2SO4) and evaporated to give the product as a dark yellow oil (0.78 g, 75%~; TLC, Rf=0.7, chloroform:-methanol (10:1); MS, m/e=185(M+l, base), 167, 140.
c. (S)-Benzyloxycarbonyl-L-valyl-N-[2-methyl-1-(2-thiazolyl)carbonylpropyl]-L-prolinamide (For-mula VI, heterocycle containing X, N and Q=2-thiazolyl).
Amino ketone prepared according to the ` procedure of Example 14b (0.73 g) was dissolved in dichloromethane t25 ml). Sequentially added to the solution were benzyloxycarbonyl-L-valyl-L-proline (1.38 g), l-hydroxybenzotriazole (1.07 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.76 g). The mixeure was stirred overnight at ambient temperature under nitrogen. The reaction mixture was diluted with dichloromethane, washed (saturated NaHCO3, lOX HCl), dried (Na2SO4~ and evaporated to give a yellow oil (2.5 g). Purification - by flash chromatography, eluting with hexane:ethyl acetate (1:1) gave the product as a solid foam (1.61 g)~ TLC, Rf=0.3, hexane:ethyl acetate (1:1); MS, m/e=515(M+l, base), 407, 331, 282, 91.
Analysis for C26H34N4O5S-0 5 H2O
Calculated: C, 59.64; H, 6.74; N, 10.70 - Found: C, 59.56; H, 6.54; N, 10.42 .
~ 35 .

d. (S)-L-Valyl-N-[2-methyl-1-(2-thiazolyl)carbonyl-propyll-L-prolinamide trifluoromethanesulfonic acid salt (Formula V, heterocycle containing X, N
and Q=2-thiazolyl).

Ketone prepared according to Example 14c (0~51 g) was dissolve~ in dichloromethane (15 ml) and was treated with trifluoromethanesulfonic acid (0.44 ml) in a single portion. The reaction mixture was stirred at ambien~ temperature for 15 min. Evapor-ation and drying under high vacuum gave a white gum (1.17 g, more than 100%). The weight of crude product in excess to lOOX yield was assumed to be trifluoro-methanesulfonic acid.
e. ~S)-14~(4-Chlorophenyl~sulfonylaminocarbonyl]-benzoyl~-L-valyl-N-12-methyl-1-(2-thiazolyl~-carbonylpropyll-L-prolinamide (Formula 1, hetero-cycle containing X, N and Q=2-thiazolyl, A=CO, L-~-phenylene, R4-R5.(So2).NH.Co-, R5-4-ClC6H4).

-.~
Orude amino ketone prepared according to the procedure of Example 14d and used without further purification (1.14 g), l-hydroxybenzotriazole (0.13 g), 4-[(4-chlorophenyl)sulfonylaminocarbonyl]benzoic acid (0.34 g) and 4-methylmorpholine (0.59 ml) were " dissolved in tetrahydrofuran and the mixture was treated with 1-~3-dimethylaminopropyl)-3-ethylcar-bodiimide hydrochloride. The mixture was stirred overnight under nitrogen. Evaporation gave a residue which was partitioned between water and ethyl acetate.
The organic phase was washed (10% HCl, water, brine), dried (MgSO4) and evaporated. Flash chromatography, `~ eluting with chloroform:methanol:acetic acid ~; 35 (100:2,5:0.5), gave the product as a white foam (0.50 g). A second purification (same solvent system as .
:
: . - - . .. .

. .
.

-.
.
.. .. ' , , :
; -: .

~77~ 1326107 above) yielded the title product as a white foam (0.43 g); TLC, Rf=0.35, chloroform:methanol:acetic acid (100:2.5:0.5); MS, m/e=702 (35Cl-M~1), 283, 282 (base), 120; HPLC, tR-8.54, Col A, FR=2, water:aceto-nitrile:tetrahydrofuran:trifluoroacetic acid ` (5~:35:15:0.1~.
: `
.
Example 15 `' 10 (S)-[4-IN'-~Phenylsulfonyl)ureido]benzoyl]-L-valyl-N-[1-(2-benzoxazoyl)carbonyl-2-methylpropyl]-L-prolin-amide IFormula I, heterocycle containing X, N and . Q=2-benzoxa~oyl, A=CO, L=~-phenylene, R4=R5.S(o2~.-; 15 NH.CO.NR6-, R5-C6H5, R6=H).

.
~ a. 4-[N'-(Phenylsulfonyl)ureido]benzoic acid.
y To a stirred solution of p-aminobenzoic acid (3.48 g) and 4-methylmorpholine (2.75 ml) in distilled tetrahydrofuran (110 ml) was added phenyl-sulfonyl isocyanate (4.65 g). The reaction mixture, which warmed slightly upon addition, was stirred for ~ 25 18 hr, diluted with lN HCl, and extracted with methy--. lene chloride. The organic extracts were washed (lN
HCl (twice), brine), dried (Na2SO4), filtered and evaporated eo afford a yellowish solid. This solid was triturated with ether and filtered to afford the product as a white solid t5.26 g, 65%); TLC, Rf~0.25, . methanol:chloroform:acetic acid (5:95:1); MS, 321(M+1), 303, 277, 257, 184, 164, 160, 159, 158, 141, 140, 139, 138, 137, 120, 94.

`' ':

-78- 1 32~07 b. (lS)-Benzyloxycarbonyl-L-~alyl-N-[1-(2-benz-oxazoyl)hydroxymethyl-2-methylpropyl]-L-pro-linamide (Formula XIV, heterocycle containing X, N and Q=2-benzoxazoyl).
To a stirred solution of ethanol (42.3 ml) in chloroform (44 ml) at 0~ was added dropwise acetyl chloride ~46.5 ml) over 25 min. The mixture was stirred an additional 10 min. Cyanohydrin prepared as described in Example 4a (10.0 g), was added to the mixture, followed by an additional volume of chloro-form (44 ml). The reaction mixture was stirred at 0 ~or 3 hr and the solvents evaporated to afford a white foam which was dissolved in ethanol (100 ml). To this ethanol~c solution was added 2-aminophenol (7.14 g), and the resulting brown mixture was heated to 60 with stirring under nitrogen for 45 min. The reaction ` mixture was cooled, diluted with ether, washed (lN
- NaOH (5 times), brine), dried (Na2SO4/K2CO3 (2:1 v/v)), and evaporated to obtain a brown foam (10.3 g).
" The crude material was purified by flash chroma-tography, eluting with acetone:hexanes (35:65), to afford the product (4.92 g); TLC, Rf=0.24, methanol:
chloroform t5:95); MS, m/e=551(M~1), 331, 148, 108, ;~ 25 91.
Analysis for C30H38N4O6 0 50 H2O:
Calculated: C, 64.39; H, 7~02; N, 10.01 Found: C, 64.29; H, 6.87; N, 9.86 c. (lS)-L-Valyl-N-[1-(2-benzoxazolyl)hydroxymethyl-2-methylpropyl]-L-prolinamide (Formula XV, heterocycle containing X, N and Q=2-benzoxazolyl).

A mixture of 10% (w/w) palladium on carbon (800 mg, 50X (wlw) water wet) and the product from ` Example 15b (4.90 g) in ethanol (250 ml) was hydro-. , . ~ , :. . .
.

i326~7 genated in a shaker at 3.4 bar for 2 hr, after which time an additional portion of catalyst (0.500 g) was added. The mixture was hydrogenated in a shaker at 3.4 bar for an additional 2 hr, filtered through diatomaceous earth and evaporated to afford the prod~ct as a solid ~3.67 g, 99%); TLC, Rf=0.42, ` methanol:chloroform (5:95); MS, m/e=445(M+29), -~ 418(M~2), 417(N+l~.

- 10 d. (lS)-~4-lN'-tPhenylsulfonyl)ureido)benzoyl]-L-valyl-N-[1-(2-benzoxazolyl)hydroxymethyl-2-methylpropyl]-L-prolinamide ~Formula II~, heterocycle containing X, N, and Q=2-benzoxa-zolyl, A=CO, L=~-phenylene, R4=R5.S(O2).NH.CO.-NR6_, R5=C6H5, R6= H).
~.
1-(3-Dimethylaminopropyl~-3-ethylcarbodi-imide hydrochloride (190 mg) was added to a solution of the product of Example 15c (380 mg), l-hydroxy-benzotriazole (140 mg), and 4-lN'-(phenylsulfonyl)-ureido]ben20ic acid (320 mg) in dimethylformamide (5 ` ml) and the solution stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed (lN HCl (three times), brine), dried (MgSO4), and evaporated. The crude product was flashchromatographed, eluting with ethyl acetate:chloro-form:acetic acid (50:50:1) to afford the product as a solid (460 mg); TLC, Rf-0.14, methanol:chloroform:
acetic acid (5:95:1).
Analysis for C36H44N6O8S 1.0 H2O.1, 3 2 Calculated: C, 57.13; H, 6.31; N, 10.51.
Found: C, 58.39; H, 6.33; N, 9.95.

- ' ' ', .
..

13261~7 e. (S)-[4-tN'-(Phenylsulfonyl)ureido]benzoyl]-L-valyl-N-[1-(2-benzoxazolyl)carbonyl-2-methyl-propyl]-L-prolinamide (Formula I, heterocycle containing X, N and Q=2-benzoxazolyl, A=CO, L~ phenylene, R4=R5.S(O2).NH.CO.NR6-, R5=C~H5, R6=H).

Dess-Martin periodinane ~440 mg) was added to a solution of t-butanol (0.048 ml) and the product of Example 15d, (370 m~ in dry methylene chloride ~2.5 ml). The mixture immediately darkened and was allowed to stir for 22 hr. The resulting suspension was diluted with methylene chloride, washed (1:1 (v/v~
saturated sodium thiosulfate/sodium bicarbonate (3 times), brine), dried (NgSO4), and evaporated to ` afford 450 mg of crude oil. This was flash chroma-tographed, eluting with ethyl acetate:dichloromethane:
acetic acid (50:50:1), then rechromatographed using ' the same system to afford the title compound (91 mg);
TLC, Rf~0.22, ethyl acetate:dichloromethane:acetic acid (50:50:1); HPLC, tR~8.46, Col B, FR~2, water:
acetonitr~le:tetrahydrofuran:trifluoroacetic acid (55:35:15:0.1); MS, m/e-640, 317, 316, 298, 245, 219, 197, 12~.
Analysis for C36H40N68S 1 H2 2 3 2 -~ Calculated: C, 56.20; H, 5.89; N, 9.83.
~`s Found: C, 56.08; H, 5.93 N, 9.33.
.
Example 16 `~ 30 ~ (S)-[4-lN'-1(4-Chlorophenyl)sulfonyl]ureido]benzoyl]-; L-valyl-N-[1-(2-benzoxazolyl)carbonyl-2-methylpropyl]-L-prolinamide (Formula I, heterocycle containing X, N and Q~2-benzoxazolyl, A-CO, L-~-phenylene, R4=R5.S-(02).NH.CO.NR6-, R5-4-ClC6H4, R6=H).

`:
,:
.

, . . . . . . .

. , . . : :
: . . . .

-81- ~ 32~ 07 a. 4-[N'-[(4-Chlorophenyl)sulfonyl]ureido]benzoic acid~

To a stirred solution of p-aminobenzoic acid ~` 5 (2.68 g) and 4-methylmorpholine (2.15 ml) in distilled tetrahydrofuran ~90 ml) was added chlorophenylsulfonyl isocyanate (4.25 g), The reaction mixeure, which warmed slightly upon addition, was stirred for 18 hr.
The reaction m~xture was acidified with lN HCl, and a flocculent precipitate formed. ~he mixture was extracted with methylene chloride, leaving much of the precipitate. Evaporating the methylene chloride solution and triturating the resulting solid with ether afforded 1.25 g of a white solid. The original solid precipitate was lixiviated with methanol, and the resulting solution was evaporated to afford a white solid which was triturated with ether to afford an additional 4~90 g (total yield 5.15 g, 89X) of white solid; TLC, Rf=0.21, methanol:chloroform:acetic acid (5:95:1); MS, m/e=355(M+1), 220, 219, 218, 192, 177, 175, 164, 139, 138, 120, 94.

b. (lS)-14-lN'-[(4-Chlorophenyl)sulfonyl]ureido3-benzoyl]-L-valyl-N-[1-(2-benzoxazolyl)hydroxy-methyl-2-methylpropyl~-L-prolinamide (Formula III, heterocycle containing X, N and Q=2-benz-oxazolyl, A-CO, L~-phenylene, R4sR5.S(o2).NH.-CO.NR -, R ~4-ClC6H4, R6=H).

1-(3-Dimethylaminopropyl)3-ethylcarbodi-imide hydrochloride (210 mg) was added to a solution of the product of Example 15c (360 mg), 4-dimethyl-aminopyridine (130 mg), and 4-[N'-[(4-chlorophenyl)-sulfonyl~ureido~benzoic acid (507 mg) in tetrahydro-furan t5 ml); and the solution stirred at room tem-perature for 16 hr. The reaction mixture was diluted ;' .
. . ~ . ~., ;, ' ~ ' :

...:
'- :. . ..
... .

13261~7 with ethyl acetate, washed (distilled water (3 times), lN HCl, saturated sodium bicarbonate, brine~. The bicarbonate wash was acidified to pH=l and washed three times with ethyl acetate. The combined organic phases were washed (brine), dried (Na2SO4), and evaporated. The crude product was flashed chromato-graphed, eluting with tetrahyd~ofuran:chlosoform:ace-tic acid (70:30:1). The resulting material was filtered through silica gel using tetrahydrofuran:
chloroform:acetic acid 130:70:1 to 100:0:1) to afford the prod~ct (350 mg~ as a solid; TLC, Rf=0.55, tetra-hydrofuran:chloroform:acetic acid (80:20:1); MS, m/e=247, 197, 163.
Analysis for C37H41ClN6OgS.4 0 H2O.5 0 3 2 Calculated: C, 48.94; H, 6.03; N, 7.29 Found: C, 48.64; H, 5.16; N, 7.53 c~ (S)-[4-lN'-1(4-Chlorophenyl)sulfonyl]ureido]ben-zoyl3-L-valyl-N-[l-t2^benzoxa~olyl~carbonyl-2-methylpropyl]-L-prolinamide (Formula I, hetero-cycle containing X, N and Q=2-benzoxazolyl, A=CO, L=p-phenylene, R4=R5.S(O2).NH.CO.NR6_, R5=4-`' ClC6H4, R6=H).

Dess-Martin periodinane t500 mg), was added to a solution of t-butanol ~0.055 ml) and the product - from Example 16b (440 mg) in dry methylene chloride (3 ml). The mixture immediately darkened and was allowed to stir for 22 hr. The resulting suspension was diluted with ethyl acetate, washed (1:1 (v/v) saturated sodium thiosulfate:sodium bicarbonate (3 times)), dried tMgSO4), and evaporated to afford 570 mg of an oil. This was flash chromatographed, eluting with acetone:methylene chloride:acetic acid (60:40:1), to afford the title compound (95 mg); TLC, Rf=0.50, methanol:chloroform:acetic acid (10:90:1);

, _ . . . .

::
.

.
:

-83- ~326~ 07 HPLC, tR-14.68, Col B, FR=2, water:acetonitrile:
tetrahydrofuran:trifluoroacetic acid (55:35:15:0.1);
MS, m/e=317, 316, 219, 192, 120.
Analysis for C36H39ClN6O8S.l.0 CH3CO2H:
Calculated: C, 56.26; H, 5.34; N, 10.36.
- Found: C, 56.23; H, 5.50; N, 10.59.

Example 17 (S)-~4-lN'-[(4-Chlorophenyl)sulfonyl3ureido3benzoyl]-L-valyl-N-11-15-(methoxycarbonyl)benzoxazol-2-yl]car-bonyl-2-methylpropyll-L-prolinamide (Formula I, heterocycle containing X, N and Q=5-(methoxycarbonyl)-benzoxazol-2-yl, A=ICO, L=~-phenylene, R4=R5.S(o2).NH.-CO.NR6, R5=4-ClC6H4, R6-H).

a. (S)-L-Valyl-N-[1-15-(methoxycarbonyl)benzoxazol-2-yl]carbonyl-2-methylpropyl]-L-prolinamide (For-mula V, heterocycle containing X, N, and Q=5-(methoxycarbonyl)benzoxazol-2-yl).

To a stirred solution of the product of Example 8b (1.00 mg) in methylene chloride (~ ml) under nitrogen was added dropwise trifluoromethanesul-fonic acid (0.73 ml). After 10 min the reaction mixture was diluted with dichloromethane and washed three times with distilled water. The pH of the resulting solution was ad~usted to pH 8 by the ad-dition of a solution of saturated sodium bicarbonate(25 ml). The basic solution was vigorously extracted with dichloromethane six times. Sodium chloride (10 g) was added to the remaining aqueous layer, and it was extracted twice with dichloromethane. All the organic extracts were combined, dried (Na2SO4) and ,;
... , ` `` ' :
' ~` ,' -~

.. .

-84- 13261~7 evaporated to afford the product (620 mg); TIC, Rf=0.20, methanol:chloroform, (5:95).

b. (S)-14-lN`-I(4-Chlorophenyl)sulfonyl]ureido]ben-zoyl~-L-valyl-N-[l-t5-(methoxycarbonyl)benzoxa-zol-2-yl]carbonyl-2-methylpropyl]-L-prolinamide (~ormula 1, heterocycle containing X, N and Q=5-(methoxycarbonyl)benzoxazol-2-yl, A-C0, L=p-phenylene, R4=R5.S(2)NH.C0.NR6, R5=4-ClC6H4, ~6=H).

3-Dimethylaminopropyl)3-ethylcarbodi-imide hydrochloride (100 mg), was added to a solution of the product of Example 17a (225 mg), l-hydroxy-benzotris201e (70 mg), and 4-~N'-1(4-chlorophenyl)-sulfonyllureido]benzoic acid (190 mg) in dichloro-methane (3 ml) and the solution stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed (lN HCl (3 times), brine), dried (NgS04), and evaporated The crude produc~ was purified by flash chromatography, eluting with ace~one:methylene chloride:acetic acid (10:90:1), to afford the title compound (271 mg) as a solid; TLC, Rf-0.14, acetone:dichloromethane:acetic acid t20:80~ HPLC, tRsl3.47, Col A, FR=2, water:ace-tonitrile:tetrahydrofuran:trifluoroacetic acid ~55:35:15:0.1); MS, m/es699, 374, 245, 219, 197, 178, 120.
Analysis for C38H44ClN6olos~3 7 H20 0 70 CH3C2H
30Calculated: C, 51.55; H, 5.62; N, 9.15 Found: C, 51.40; H, 4.97; N, 9.48 `~:

.
' : ~ , . ... . ..
:
, -85- 13261~7 Example 18 [4-[(Trifluoromethylsulfonyl)amino]benzoyl]-L-valyl-` N-[1-[5-(methoxycarbonyl)benzoxazol-2-yl]carbonyl-2-methylpropyl]-L-prolinamide (Formula I, heterocycle containing X, N and Q=5-(methoxycarbonyl)benzoxazol-- 2-yl, A=CO, L--~-phenylene, R4=CF3.S~o2).NH-).

a. Ethyl 4-[(trifluoromethylsulfonyl)amino]benzoate.
Trifluoromethanesulfonic anhydride (4.1 ml) was added dropwise to a precooled (0) solution of ethyl p-aminobenzoate (3.3 g) in dichloromethane (50 ml) under nitrogen. The reaction mixture was stirred for 1 hr at 0, then was allowed to warm to room temperature and was stirred for 1 hr. After the `~ reaction mixture was evaporated, ethyl acetate (125 ml) was added to the residue; and the resultant organic solution was washed (lN HCl, then brine), dried (MgSO4), and evaporated. The residue was purified by flash chromatography, eluting with chloro-form:methanol (95:5), to give the product as a white powder (1.27 g); TLC, Rf-0.37, chloroform:methanol (90:10?.
b. 4-l(Trifluoromethylsulfonyl)amino]benzoic acid.

A solution of lN NaOH (8.4 ml) was added to a stirred solution of the product of Example 18a (1.25 g) in methanol (25 ml). Water (2 ml) was added, and the reaction mixture was stirred overnight.
After the methanol was distilled off under water aspiration vacuum, the resulting aqueous residue was diluted with water (20 ml). The aqueous solution was washed with ethyl acetate, made acidic (pH 2) with lN
~ HCl, and extracted with ethyl acetate (total=40 ml).

:.

. ` ' ~'` .
- - ' `

.
.

13261~7 The organic phase was dried (MgSO4) and evaporated to give the product as a white powder (1.05 g~; TLC, Rf=0.4, chloroform:methanol:acetic acid (96:4:0.2).

c. ~S)-L-Valyl-N-11-[5-(methoxycarbonyl)benzoxazol-2-yl3carbonyl-2-methylpropyl]-L-prolinamide (For-mula V, heterocycle containing X, N, and Q=5-(methoxycarbonyl)benzoxazol-2-yl).

~- 10 To a stirred solution of the product of ExEmple 8b (750 mg) in methylene chloride (5 ml) under nitrogen was added dropwise trifluoromethanesulfonic acid (0.53 ml). After 20 min the reaetion mixture was - diluted with dichloromethane and washed three times with distilled water. Sodium chloride (5 g) was added to ehe combined aqueous layers and the resulting ~` solution was adjusted to pH 8 by the addition of a solution of saturated sodium bicarbonate ~20 ml). The basic solution was vigorously extracted with dichloro-methane eight times. The organic layers were com-` bined, dried (Na2SO4) and evaporated to afford the product (420 mg); ~LC, Rf=0.28, methanol:chloroform ` (5:95).

d. 14-l(Trifluoromethylsulfonyl)amino]benzoyl]-L-valyl-N-11-l5-(methoxycarbonyl)benzoxazol-2-yl~
carbonyl-2-methylpropyl]-L-prolinamide (Formula I, heterocycle coneaining X, N and Q-5-(methoxy-~`~ carbonyl)benzoxazol-2-yl, A~CO, L=~-phenylene, `~ 30 R4=CF3.S(o2).NH-).

``; 1-(3-Dimethylaminopropyl)-3-ethylcarbodi-imide hydrochloride (240 mg) was added to a solution of the product of ExamPle 18c (420 mg), 4-dimethyl-aminopyridine (110 mg), and 4-~(trifluoromethyl-sulfonyl)amino]benzoic acid (340 mg) in tetrahydro-,`'-~.

., ,: :
; ~ , ' : ; .~
". . - ~ .,:
. - - ~.. .
:~:

-87- 1326~7 furan (3 ml); and the solution stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed (lN HCl (3 times), brine), dried (MgS04), and evaporated. The crude product was purified by flash chromatography, eluting with methanol:chloroform:acetic acid (20:80:1), to afford the title compound (330 mg) as a solid; TLC
Rf=0.50, methanol:chloroform:acetic acid (5:95:1);
HPLC, tR-15.61, Col A, water:acetonitrile:tetrahy-drofuran:acetic acid (55:35:15:0.1), FR=2; MS, m/e=752(M+29), 724(M+1), 706, 374, 356, 351, 323.
Analysis for ~3~H36F3N509SØ60 H20. . 3 2 `~` Calculated: C, 51.57; H, 5.20; N, 8.95.
Found: C, 51.29: H, 5.07 N, 8.97.

Example 19 S-14-t(4-Chlorophenyl)sulfonylaminocarbonyl]benzoyl]-L-valyl-N-[1-[5-(aminocarbonyl)benzoxazol-2-yl]car-bonyl-2-methylpropyl]-L-prolinamide (Formula I, heeerocycle containing X, N and Q=5-(aminocarbonyl)-_ benzoxazol-2-yl, A=CO, L=~-phenylene, R4=R5.S(o2).-NH.CO-, R5=4-ClC6H4).

:
Method A

Materisl prepared as described in Example 6 and estimated to contain at least 95X of the (S)-dia-stereomer (200 mg) was dissolved in hot chloroform (15 ml), filtered, and diluted to a total volumn of 25 ml - with hot chloroform. Toluene (5 ml) was added until the solution just turned cloudy and a few drops of chloroform were added resulting in a clear solution.
The solution was allowed to cool slowly. After 4 days, the supernatent was removed by filtration and ~ -88- 1326107 the crystallized solid was dried under nitrogen to afford 101 mg white solid; mp 165-180; []D5 =-73.2 (c=2.5, CH30H).
Method B

a. Benzyloxycarbonyl-L-valyl-L-proline t-butyl ester.

N-Benzyloxycarbonyl-L-valine (121.3 g), l-hydroxybenzotriazole ~130.5 g) and dry dimethyl-formamide (DMF) (800 ml) were placed in a 5 liter, 3-necked flask equipped with a mechanical stirrer, thermometer, and a calcium sulfate drying tube, under nitrogen atmosphere. The mixture was cooled to 0 for 15 min and proline t-butyl ester (82.6 g) in dry DMF (800 ml) was added at a fast dropwise rate over 2 h while the ~emperature of the reaction mixture was maintained at 0. Dicyclohexylcarbodiimide (109.4 g) in dry DMF (400 ml) then was added in one portion to the reaction mixture. The reaction was stirred at 0 for 3 h, allowed to warm to room temperature gradually over 1 h, and stirred for 48 h, whereupon the reaction was shown to be complete by TLC tRf=0.55, ~` chloroform:ethyl acetate (85:15~. The reaction mixture was chilled in ice/water and filtered cold to ` remove the precipitated dicyclohexyl urea. The DMF
~-~ was evaporated using a mechanical vacuum pump and at a ` maximum bath temperature of 40. The remaining oil was diluted with ethyl acetate (2 liter), chilled, and refiltered to remove additional dicyclohexyl urea.
The ethyl acetate solution was washed (20% (w/v) citric acid solution (twice), saturated sodium ~`~ chloride solution, saturated sodium bicarbonate ~` solution (twice), and saturated sodium chloride solution), dried (MgSO4), and evaporated to afford ~` crude benzyloxycarbonyl-L-valyl-L-proline t-butyl ester as an amber oil (208.3 g, 100%).

~ _ . . . ..
,:
- . , .

.- : -. .
:' .
. ~ . . . ;.~ ,.

-89- 13261~7 b. L-Valyl-proline t-butyl ester.

A solution of benzyloxycarbonyl-L-valyl-L-proline t-butyl ester (51.8 g) dissolved in absolute ethanol (1 liter) was placed in a 2 liter hydrogena-tion bottle. The reaction mixture was purged with nitrogen, and 10~ (w/w) palladium on carbon catalyst (10 g, 50X (w/w) water wet) was added. The reaction was placed on a large shaker apparatus and sha~en at room temperature under a hydrogen atmosphere (3.4 bar). After 1 h, hydrogen uptake ceased. The re-action mixture was checked by TLC lchloroform:ethyl acetate (85:15)] and shown to contain considerable starting material (Rf=0.55). Fresh catalyst (10 g) was a~ded, and the reaction was placed back on the apparatus for another 4 h, at which point hydrogen uptake ceased. TLC of the reaction mixture showed complete absence o$ starting material. The reaction mixture was filtered through a pad of diatomaceous earth, and the filter cake was wa~hed with ethanol.
Evaporation of the ethanol from the condensed solution left a cloudy yellow oil. This oil was dissolved in -ether ~1 liter), filtered to remove a small amount of precipitate (dicyclohexylurea) and evaporated to give `25 crude L-valyl-L-proline t-butyl ester as a yellow oil (32.1 g, 93Z).
~ `
c. [4-[(4-Chlorophenyl)sulfonylaminocarbonyl]ben-;zoyll-L-valyl-L-proline t-butyl ester.
; 4-Dim~thylaminopyridine (16.4 g) was added to a solution of 4-1(4-chlorophenyl)sulfonylamino-; carbonyl]benzoic acid (45.6 g) in methylene chloride (250 ml). The mixture was stirred 15 min before amine from Example l9b (39.9 g) in dichloromethane (250 ml) : and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide .~
, .~

.

, , (28.3 g), successively, were added. The reaction mixture was stirred 16 h and additional amine (1.1 g) and carbodiimide (1.5 g) were added to the reaction mixture. After an additional 3 h, the reaction was evaporated to afford a thick, grey syrup. This was dissolved in ethyl acetate, washed (20% w/w citric acid (3 times), brine (4 times)), dried (MgSO4), and evaporated. The crude material was flash chromato-graphed, eluting with methanol:methylene chloride (gradient: 0:1 (1.5 liter), 2:98 (1.5 liter), 4:96 (1.5 liter), 5:95 (4 liter)), to afford 14-[(4-chlorophenyl)sulfonylaminocarbonyl]benzoyl]-L-valyl-L-proline t-butyl ester (65.5 g, 73%) as a white foam;
TLC, Rf=0.50, methanol:dichloromethane:acetic acid (2:98:1).

d. t4-t(4-Chlorophenyl)sulfonylaminocarbonyl3ben-zoyl~-L-valyl-L-proline (Formula IXa, A=CO, L=~-phenylene, R4=R5.St~2).NH.CO-, R5S4-ClC6H4).
-`~; The product from Example l9c (65.5 g) was dissolved in trifluoroacetic acid (200 ml) with ` stirring under a nitrogen atmosphere at O. After one ~` hour the reaction mixture was cooled to -15 for 16 h, ``~ 25 after which time the reaction was poured into ice water (2 liter) with vigorous stirring. The precipi-` tate was filtered, washed with three portions of cold water and dried under reduced pressure. The crude product was redissolved in trifluoroacetic acid ~200 ml~ and stirred at room temperature 18 h. The reaction mixture was poured into of ice water (1.5 liter) with vigorous stirring. The precipitate was filtered and dried under high vacuum to afford the acid (59.7 g); TLC, Rf=0.05; methanol:chloroform:acetic acid (5:95:1). For further purification, the above ` acid (59.7 g) and calcium oxide (6.25 g) were dissol-ved in water (500 ml) and tetrahydrofuran (500 ml), .

and heated at 55-60 foI 0.5 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The aqueous phase was decanted from the gummy residue and lyophilized to afford a yellow-white powder (47.3 g). This material was crystallizedfrom methanol:water and converted bac~ into the free acid by dissolving it in water and ereating the solution with lN HCl (pH 2) and filtering the precipi-tated solid.
e. N-Benzyloxycarbonyl-L-valinal.

To a solution of the product of Example lc (27.5 g) in acetone (1.7 liter) was added p-toluene-sulfonic acid mono-hydrate (1.0 g) and the resulting solution stirred for 28 h. The solvents were evapo-rated; and the residue was dissolved in ether, washed (saturated NaHCO3 (3 times), brine)), dried (MgSO4) and evaporated to afford the aldehyde (20.6 g); TLC, Rf=0.48, methanol:chloroform (5:95): MS, mle=~36(M+l), 192, 91.

f. t3S)-3-tBenzyloxycarbonyl)amino-2-hydroxy-4-methylpentanenitrile (Formula XIIIa, W=CN).
;;~ 25 `~ A 500 ml round bottomed flask with stirrer was dried under vacuum and purged with nitrogen. The `-~ flask was charged with methylene chloride (265 ml) followed by the addition of the aldehyde product of Example l9e t20.6 g) and triethyl amine (7.40 ml).
. Acetone cyanohydrin (24.0 ml) was added in one por-tion. The reaction mixture was stirred for 6 h and the solvent evaporated. The crude product was dis-solved in ether, washed (water (3 times), brine), . 35 dried (MgS04), and evaporated. The resulting crude .~

t3~6~07 oil was flash chromatographed, eluting with methylene chloride:methanol:NH40H (99:1:0.1) to afford the cyanohydrin (18.Q g, 78X) as a yellow solid; TLC, Rf=0.53, acetone:hexanes ~50:50).

g. (2S)-2-[2-(Benzyloxycarbonyl)amino-l-hydroxy-3-methylbutyl3benzoxazole-5-carboxamide (Formula XIVa, heterocycle containing X, N and Q=5-(aminocarbonyl)ben~oxazol-2-yl~.
1~ .
A 1 liter flask with stirrer was dried under vacuum and purged with nitrogen. The flask was charged with freshly distilled acetyl chloride (98.0 ml) and chloroform ~100 ml) and cooled in an ice bath.
Ethanol ~89.0 ml) was added dropwise over 45 min maintaining the temperature below 15. Afeer cooling to 5, a solution of the product of Example l9f (12.0 g) in chloroform (100 ml) was added dropwise over the course of 10 min. The reaction mixture was allowed to stir for 2 h in an ice bath and the solvent evaporated ~ at 0 to afford a tan foam (14.1 g, 100~): TLC, :~ after partitioning an aliquot between ethyl acetate r _ and saturated NaHC03 to fonm the free imino ether, RfS0.40, acetone:hexanes (50:50); MS, m/e=309(M~l).
? 25 This foa~ was dissolved in absolute ethanol (230 ml) ` and 3-amino-4-hydroxybenzamide (7.30 g) was added.
` The mixture was refluxed for 1.5 h and the solvent - evaporated to afford a brown solid. The solid residue was dissolved in 500 ml ethyl acetate, washed (lN HCl 30 saturated with NaCl, saturated NaHCO3tNaCl, brine), dried (MgSO4), and evaporated. This residue was dissolved in methanol, adsorbed onto diatomaceous earth, and flash chromatographed, eluting with acetone:hexanes (50:50), to afford the alcohol (7.15 g, 39%) as a tan solid; TLC, Rf=0.11, acetone:hexanes (50:50); MS, m/e=290, 246.

B`

. .

~93- i32~07 h. (2S)-2-(2-Amino-l-hydroxy-3-methylbutyl)benzoxazol-5-carboxamide (Formula XVa, heterocycle contain-ing X, N and Q=5-(aminocarbonyl)benzoxazol-2-yl).

A mixture of 10% (w/w) palladium on carbon (1.26 g, 50~ (w/w) water wet) and the product from Example l9g (5~00 g), in ethanol (63 ml) was hydro-genated in a shaker at 3.4 bar for 18 h. The mixture was filtered through diatomaceous earth and the solvent evaporated to afford ~he amine (3.13 g, 95X) as a tsn solid; TLC, Rf=0~20, methylene chloride:-meehanol:NH40H (95:5:0.5); MS, m/e=264 (M+l).

i. (lS)-t4-~(4-Chlorophenyl)sulfonylaminocarbonyll-benzoyl]-L-valyl-N-[1-[5-(aminocarbonyl)benzoxa-zol-~-yllhydroxymethyl-2-methylpropyl]-L-prolin-amide (Formula IlI, heterocycle containing X, N
and Q=5-(aminocarbonyl)benzoxazol-2-yl, A=C0, L=p-phenylene, R4=R5.S(o2).NH.Co-, R5=4-ClC6H4).
- - 1-(3-Dimethylaminopropyl)-3-ethylcarbodi-imide hydrochloride (1.57 g) was added to a solution _ of the product of Example l9h (1.57g), l-hydroxybenz-- triazole (1.01 ~) and the acid product of Example 19d (4.00 g) in dimethylformamide (75 ml) and the solution stirred at room temperature for 60 h. The solvent was r evaporated and ehe brown oil washed with lN HCl ` saturated with NaCl, forming a tan precipitate. After ;~the precipitate was filtered and a portion of the .30 solid ~750 mg) was removed, the crude precipitate was -dissolved in methanol, adsorbed onto diatomaceous earth and purified by flash chromatography, eluting with methylene chloride:methanol:NH40H (gradient 85:15:1 to 70:30:1), to afford the alcohol (3.58 g, 59~) as a tan solid; TLC, Rf=0.22, methylene chloride:methanol acetic acid (90:10:0.2); MS, m/e=421.
'~3 ~94~ 1326107 j. (S)-[4-[(4-Chlorophenyl)sulfonylaminocarbonyl~-benzoyl]-L-valyl-N-[1-[5-(aminocarbonyl)benzoxa-zol-2-yl)carbonyl-2-methylpropyl]-L-prolinamide ; (Formula I, heterocycle containing X, N and Q=5-(aminocarbonyl)benzoxazol-2-yl, A=CO, L=~-phenylene, ~4=R5.S(o2).NH.Co-, R5=4-ClC6H4).

To a solution of alcohol prepared in a similar manner to that described in Example l9i, above, (50 mg) and 1-t3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (183 mg) in dimethylsul-phoxide (1.0 ml) and toluene (1.0 ml) was added dichloroacetic acid (8~2 mg, 0.0052 ml). The mixture was allowed to stir for 16 h, then additional di-chloroacetic acid (0.011 ml) was added and stirring continued for an additional 24 h. The reaction mixture was dissolved in chloroform, washed (1~ HCl, . brine), dried (MgSO4), and the solvents evaporated to " 20 afford the title compound (42 mg).
''.
-:~

` :~

:"

.
- , . . ';
.

` ` -gs- 1326107 R--L--A--~ ~N~

It~ L--A--N~ ~X)~

.

i ~--L--A--N~,X~NX~ N

. ~ .
S` ~X~ ~

:

,.: . . . .
. . . ` . .

.

. ~_S

U 10~_ ' ~ 3 S ~_ z o~

~ t g /~z s U

~ s '~ ' Z"

.

. .
: .

~97~ 13261 07 m- Il N ~l, OH
Y~

~ LC~--N ~ XOrH~x ,.` / ~ l ¦ ? F~b OH
: X'~

F~
x~n ~ .. ~X

S~eme 111 C~Z--N~ CB~--NX~W
H H H OH
~ Xllla H OH X~~(X31~
XlVa XVa A~ OH+XVa_ 111 IXa OH+ XVa~ml Xb IV

Scheme Iv 1326107 CBZ--N~ ~OCH, . XX
O ~CH, CB~ Nl~o X;~Q XXI
`'`-H~ XXI I
. H

.:

H--~X~ XXIII

t,

Claims (17)

1. A compound of formula I:

I

wherein the group -Q- is selected from a group con-sisting of (i) ortho-phenylene, optionally bearing one or two substituents independently selected from a group consisting of halogeno, nitro, an amino group of formula -NRgRh, an acylamino group of formula -NHCORm, hydroxy, an acyloxy group of formula -OCORn, (1-4C)-alkoxy, (1-4C)alkyl, trifluoromethyl, carboxy, cyano, [(1-4C)alkoxy]carbonyl, an aminocarbonyl group of formula -CONRpRq (including formula -CONR? when Rp=Rq), sulfo, sulfonamido of formula SO2NRiRj and (1-3C)hydroxyalkyl; and (ii) a cis-vinylene group of formula -C(Ra)=C(Rb)- wherein Ra and Rb are each independently selected from a group consisting of hydrogen, nitro, an amino group of formula -NRgRh, an acyloxy group of formula -OCORn, (1-4C)alkoxy, (1-6C)alkyl, trifluoromethyl, carboxy, cyano, [(1-4C)alkyoxy]carbonyl, an aminocar-bonyl group of formula -CONRpRq (including formula -CONRp2 when Rp=Rq), a hydroxymethyl group, and phenyl optionally bearing one or two substituents chosen from a group consisting of halogeno, nitro, (1-4C)alkoxy, (1-4C)alkyl and trifluoromethyl;
Rg, Rh, Ri, Rj, Rm, Rp and Rq are each independently slelected from a group consisting of hydrogen and (1-4C)alkyl;
Rn is (1-4C)alkyl;
X is selected from a group consisting of oxygen and sulfur;
A is selected from a group consisting of -CO-, -NH.CO- and -O.CO-;

L is selected from a group consisting of phenylene, (1-6C)alkanediyl, (2-6C)alkenediyl and phenylene(1-3C)alkyl optionally containing one double bond in the alkyl portion, provided that a carbon included in a double bond of an alkenediyl or included in an optional double bond of a phenylenealkyl group is not directly bonded to an oxygen or nitrogen atom of group A: and R4 is selected from a group consisting of an acylsulfonamide of formula R5.S(O2).NH.CO-, an acysulfonamide of formula R5.CO.NH.S(O2)-, a sulfonyl-urea of formula R5.NH.CO.NH.S(O2)-, a sulfonylurea of formula R5.S(O2).NH.CO.NR6-, and a trifluoromethyl-sulfonamide of formula CF3.S(O2).NH- wherein R5 is selected from a group consisting of (1-10C)alkyl, trifluoromethyl, (3-10C)cycloalkyl, (6 and 10C)aryl optionally substituted by l to 3 members of a group consisting of halogeno, nitro, amino, dimethylamino, hydroxy, methyl, trifluoromethyl, carboxy, phenyl, formylamino and [(1-5C)alkylcarbonyl]amino;
and an aromatic heterocyclic group selected from furyl, thienyl, pyridyl and pyrimidinyl, in which up to 3 carbons of the aromatic system may bear a substituent group independently selected from a group consisting of halogeno and trifluoromethyl; and R6 is hydrogen or methyl; and pharmaceutically acceptable base-addition salts thereof.

2. A compound as claimed in Claim 1 wherein an optional substituent on Q when Q is ortho-phenylene is selected from a group consisting of fluoro, chloro, bromo, nitro, an amino group of formula NRgRh, an acylamino group of formula -NHCORm, hydroxy, an acyloxy group of formula -OCORn, methoxy, ethoxy, propoxy, isopropoxy, t-butoxy, methyl, ethyl, propyl, isopropyl, 2-methylpropyl, t-butyl, trifluoro-methyl, carboxy, cyano, methoxycarbonyl, ethoxycar-bonyl, t-butoxycarbonyl, an aminocarbonyl group of formula -CONRpRq, sulfo, sulfonamido of formula SO2NRiRj, hydroxymethyl, 2-hydroxyethyl, and 1,1-dimethylhydroxymethyl, wherein Rg, Rh, Ri, Rj, Rm, Rp and Rq are each independently selected from a group consisting of hydrogen, methyl, ethyl, propyl, iso-propyl, 2-methylpropyl and t-butyl, and Rn is selected from a group consisting of methyl, ethyl, propyl, isopropyl, 2-methylpropyl and t-butyl; Ra and Rb are each independently selected from a group consisting of hydrogen, nitro, an amino group of formula -NRgRh, an acyloxy group of formula -OCORn, methoxy, ethoxy, propoxy, isopropoxy, t-butoxy, methyl, ethyl, propyl, isopropyl, butyl, 2-methylpropyl, t-butyl, trifluoro-methyl, carboxy, cyano, methoxycarbonyl, ethoxycar-bonyl, t-butoxycarbonyl, an aminocarbonyl group of formula CONRpRq, hydroxymethyl, and phenyl wherein the phenyl optionally bears one or two substituents chosen from a group consisting of fluoro, chloro, bromo, nitro, methoxy, ethoxy, propoxy, isopropoxy, t-butoxy, methyl, ethyl, propyl, isopropyl, 2-methylpropyl, t-butyl and trifluoromethyl, wherein Rg, Rh, Rp and Rq are each independently selected from a group consist-ing of hydrogen, methyl, ethyl, propyl, isopropyl, 2-methylpropyl and t-butyl, and Rn is methyl, ethyl, propyl, isopropyl, 2-methylpropyl or t-butyl;
R5 is selected from a group consisting of methyl, ethyl, propyl, isopropyl, t-butyl, 4-meth-ylpentyl, trifluoromethyl, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl, phenyl, naphthyl (in which an optional substituent on the phenyl or naph-thyl is fluoro, chloro, bromo, nitro, amino, di-methylamino, hydroxy, methyl, trifluoromethyl, car-boxy, phenyl, formylamino, acetylamino, 2-methylpro-panoylamino or 2,2-dimethylpropanoylamino) furyl, thienyl, pyridyl and pyrimidinyl optionally substi-tuted on the aromatic heterocyclic group by fluoro, chloro, bromo or trifluoromethyl; and L is selected from a group consisting of p-phenylene, m-phenylene, methylene, ethan-1,2-diyl, ethan-1,1-diyl, propan-1,3-diyl, propan-1,2-diyl, propan-2,2-diyl, butan-1,4-diyl, 2-methylpropan-2,3-diyl, 2-methylpropan-1,2-diyl, pentan-1,5-diyl, ethen-1,2-diyl, propen-1,2-diyl, propen-1,3-diyl, buten-1,4-diyl, but-2-en-1,4-diyl, penten-1,5-diyl,

3,3-dimethylpropen-1,3-diyl, p-phenylenemethyl, 2-(p-phenylene)ethyl, 2-(p-phenylene)-2-propyl, and 2-(p-phenylene)ethenyl.

3. A compound as claimed in Claim 2 wherein an optional substituent on Q when Q is o-phenylene is chloro, dimethylamino, acetylamino, hydroxy, acetoxy, methoxy, methyl, trifluoromethyl, carboxy, cyano, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylamino-carbonyl, aminosulfonyl, dimethylaminosulfonyl or hydroxymethyl;
Ra and Rb are each independently selected from a group consisting of hydrogen, dimethylamino, acetoxy, methoxy, methyl, trifluoromethyl, cyano, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, hydroxymethyl, phenyl, chloro-phenyl, methoxyphenyl and trifluoromethylphenyl;
R4 is R5.S(O2).NH.CO-, R5.S(O2).NH.CO.NR6-, or CF3SO2NH-;
R5 is selected from a group consisting of methyl, ethyl, isopropyl, cyclopropyl, cyclopentyl, phenyl, chlorophenyl, bromophenyl, trifluoromethyl-phenyl, 1-naphthyl, 2-thienyl, 2-pyridyl and chloro-pyridyl;
R6 is hydrogen;
A is -CO-; and L is p-phenylene, ethane-1,2-diyl, ethen-1,2-diyl, p-phenylenemethyl or 2-(p-phenylene)ethenyl.

4. A compound as claimed in Claim 3 wherein an optional substituent on Q is hydroxy, methoxy, carboxy, methoxycarbonyl, aminocarbonyl or hydroxymethyl;
Ra and Rb are hydrogen;
R5 is methyl, isopropyl, phenyl or 4-chloro-phenyl; and L is p-phenylene.

5. A compound as claimed in Claim 1 containing a benzoxazole wherein X is oxygen and Q
is ortho-phenylene, an oxazole wherein X is oxygen and Q is a cis-vinylene group of formula -C(Ra)=C(Rb)-, a benzothiazole wherein X is sulfur and Q is ortho-phenylene, or a thiazole wherein X is sulfur and Q is a cis-vinylene group of formula -C(Ra)=C(Rb)- and wherein an ortho-phenylene group may optionally bear one or two sub-stituents independently selected from a group con-sisting of halogeno, nitro, an amino group of formula -NRgRh, hydroxy, acetoxy, (1-4C)alkoxy, (1-4C)alkyl, trifluoromethyl, carboxy, [(1-4C)alkoxy]carbonyl, sulfo and sulfonamido of formula SO2NRiRj; and wherein Ra and Rb are each independently selected from a group consisting of hydrogen, nitro, an amino group of formula -NRgRh, (1-4C)alkoxy, (1-6C)alkyl, trifluoromethyl, carboxy, cyano, [(1-4C)alkoxy]car-bonyl, and phenyl optionally bearing one or two substituents chosen from a group consisting of halo-geno, nitro, (1-4C)alkoxy, (1-4C)alkyl and trifluoro-methyl;
Rg, Rh, Ri and Rj are each independently selected from a group consisting of hydrogen and (1-4C)alkyl;
A is selected from a group consisting of -CO-, -NH.CO- and -O.CO-;
L is selected from a group consisting of phenylene, (1-6C)alkanediyl, (2-6C)alkenediyl and phenylene(1-3C)alkyl, optionally containing one double bond in the alkyl portion, provided that a double bond of an alkenediyl or an optional double bond of a phenylenealkyl group is not directly bonded to an oxygen or nitrogen atom of group A; and R4 is selected from a group consisting of acylsulfonamide of formula R5.S(O2).NH.CO-, acysul-fonamide of formula R5.CO.NH.S(O2)-, sulfonylurea of formula R5.NH.CO.NH.S(O02)- and sulfonylurea of formula R5.S(O2).NH CO.NR6- wherein R5 is selected from a group consisting of (1-10C)alkyl, trifluoromethyl, (3-10C)cycloalkyl, (6 and 10C)aryl optionally substituted by 1 to 3 members selected from a group consisting of halogeno, nitro, amino, dimethylamino, hydroxy, methyl, trifluoro-meehyl, carboxy, phenyl, and [(1-5C)alkylcarbonyl]-amino; and an aromatic heterocyclic group in which up to 3 carbons of the aromatic heterocyclic group may bear a substituent group independently selected from a group consisting of halogeno and trifluoromethyl; and R6 is hydrogen or methyl; and pharmaceutically acceptable base-addition salts thereof.

6. A compound as claimed in Claim 1 selected from a group consisting of:
(a) 8 benzoxazole wherein X is oxygen snd Q
is o-phenylene as defined under (i) in the definition of Q in Claim 1;
(b) an oxazole wherein X is oxygen and Q is cis-vinylene as defined under (ii) in the definition of Q in Claim 1;
(c) a benzothiazole wherein X is sulfur and Q is o-phenylene as defined under (i) in the defini-tion of Q in Claim 1; and (d) a thiazole wherein X is sulfur and Q is cls-vinylene as defined under (ii) in the definition of Q in Claim 1, and pharmaceutically acceptable base-addition salts thereof.

7. A compound as claimed in any one of Claims 1, 2, 3, 5 or 6 wherein X is oxygen; R4 is R5.S(O2).NH.CO- or R5.S(O2).NH.CO.NR6-; L is p-phenylene; A is -CO-; R5 is 4-chlorophenyl; and R6 is as defined according to Claims 1, 2, 3, 5 or 6.

8. A compound as claimed in Claim 4 wherein X is oxygen; R4 is R5.S(O2).NH.Co-; L is p-phenylene; A is -CO-; and R5 is 4-chlorophenyl.

9. A compound as claimed in Claim 1 selected from a group consisting of:
(i) [4-[(4-chlorophenyl)sulfollylamino-carbonyl]benzoyl]-L-valyl-N-[1-(5-hydroxybenzoxazol-2-yl)carbonyl-2-methylpropyl]-L-prolinamide;
(ii) [4-[(4-chlorophenyl)sulfonylamino-carbonyl]benzoyl]-L-valyl-N-[1-[5-(sminocarbonyl)benz-oxazol-2-yl)carbonyl-2-methylpropyl]-L-prolinamide;
and (iii) [4-[(4-chlorophenyl)sulfonylaminocar-bonyl]benzoyl]-L-valyl-N-[1-[5-(hydroxymethyl)benz-oxazol-2-yl]carbonyl-2-methylpropyl]-L-prolinamide;
and pharmaceutically acceptable base-addition salts thereof.

10. A salt as claimed in Claim 1 wherein said salt is made with a base forming a physiologi-cally acceptable cation.

11. A pharmaceutical composition comprising a compound of Claim 1 or a pharmaceutically acceptable base-addition salt thereof in an amount sufficient to inhibit human leukocytic elastase and a pharmaceutic-ally acceptable diluent or carrier.

12. A composition as claimed in Claim 11 wherein said composition is in the form of a liquid or powdered aerosol.

13. A compound of formula III

III
wherein R4, L, A, Q and X are defined as in Claim 1, or a salt thereof.

14. A compound of formula IV

IV
wherein R7 is selected from a group consisting of carboxy, H2N.S(O2)-, HNR6- and -NCO, and wherein R6, L, A, Q and X are defined as in Claim 1, or a salt thereof.

15. A compound of formula V

V

wherein Q and X are defined as in Claim 1, or a salt thereof.

16. A compound of formula XV

XV

wherein Q and X are defined in Claim 1, or a salt thereof.

17. A compound of formula XVa XVa wherein Q and X are defined in Claim 1, or a salt thereof.